Bicyclic compound

ABSTRACT

Provided is a pharmaceutical agent containing a compound represented by General Formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof: 
                         
wherein A represents a C 1 -C 3  linear alkylene group, in which one methylene group is optionally substituted with O or S;
 
n represents an integer of from 3 to 5;
 
X 1  and X 2  each independently represent CH or N;
 
W 1  and W 2  each independently represent a carboxyl group or a tetrazolyl group;
 
V represents a C 1 -C 8  linear or branched alkylene group, in which one methylene group is optionally substituted with O or S; and
 
R represents a substituted phenyl group, for example.

FIELD OF THE INVENTION

The present invention relates to a bicyclic compound having aheme-independent activating function for soluble guanylate cyclase and apharmaceutical agent containing the same.

BACKGROUND OF THE INVENTION

Soluble guanylate cyclase (sGC) is an enzyme which produces cyclicguanosine monophosphate (cGMP) from guanosine triphosphate (GTP), andwhich consists of a dimer of α subunit and β subunit. The β subunitbinds heme, and the iron coordinated to the heme generally interactswith the histidine residue as 105^(th) amino acid to have an inactivatedstructure. Nitrogen monoxide (NO) is known to be an major sGCstimulating factor in vivo, and according to interaction with the hemeiron which is present in β subunit of sGC and dissociating theinteraction between the heme iron and the histidine residue of βsubunit, it promotes conversion into activated form. cGMP produced byactivated sGC subsequently activates, for example, a protein kinase, oran ion channel to play various roles including relaxing vascular smoothmuscle, suppressing platelet activation, suppressing cell proliferation,and olfactory neuronal transmission. Under pathological condition,activity of sGC is lowered and decomposition of sGC occurs to suppressthe cGMP system, thus leading to contraction of, for example, vascularsmooth muscle, activation of platelet, or cell proliferation.Eventually, it may cause, for example, hypertension, pulmonaryhypertension, heart failure, endothelial function disorder,atherosclerosis, peripheral vascular disease, angina pectoris,thrombosis, myocardial infarction, erectile dysfunction, or renalfunction disorder (Non Patent Documents 1 and 2).

For activating sGC, nitrates such as nitroglycerin are widely used inclinical use. They induce the activation of sGC by supplying exogenousNO, and thus exhibit a pharmaceutical effect. However, the nitrateagents are known to have a tolerance in addition to side effects, whichis a significant problem of the pharmaceutical agent. It has beensuggested that the tolerance to the nitrate agents are based on amechanism such as reduced activity of mitochondrial aldehydedehydrogenase involved with NO release, which is different from sGC (NonPatent Document 3). Thus, a compound directly activating sGC withoutbeing related to NO release can avoid the tolerance. Further, underdisease state such as aging, hypertension, diabetes, or hyperlipidemia,it has been shown that oxidation of heme iron or decomposition of hemeis enhanced by oxidative stress to prevent the interaction between NOand heme, and thus it cannot be expected to have sufficient activationof sGC (Non Patent Document 4). As an sGC stimulating agent other thanNO, a heme-dependent direct sGC stimulating agent represented byRiociguat (Patent Document 1) is known. Those compounds can activate sGCindepending on NO, however, it is described that they cannot fullyexhibit the sGC activating property under condition for oxidizing hemeiron (Non Patent Document 5). Thus, unlike NO or Riociguat, a compoundhaving a function of directly activating sGC without depending onoxidation state of heme is believed to be effective for treatment orprevention of various disorders such as hypertension, pulmonaryhypertension, heart failure, endothelial function disorder,atherosclerosis, peripheral vascular disease, angina pectoris,thrombosis, myocardial infarction, erectile dysfunction, and renalfunction disorder.

As a compound having a function of directly activating sGC withoutdepending on oxidation state of heme, Cinaciguat and derivatives thereofare disclosed in Patent Document 2, pyrazole, triazole derivatives aredisclosed in Patent Document 3, 2,6-disubstituted pyridine derivativesare disclosed in Patent Document 4, and heterocyclic derivatives aredisclosed in Patent Document 5.

CITATION LIST Patent Documents

-   Patent Document 1: WO 2003/095451 A-   Patent Document 2: WO 2001/019780 A-   Patent Document 3: WO 2009/032249 A-   Patent Document 4: WO 2009/071504 A-   Patent Document 5: WO 2009/123316 A

Non Patent Documents

-   Non Patent Document 1: Handbook of Experimental Pharmacology,    Germany, Springer-Verlag, 2009, Vol. 191, p. 309-339-   Non Patent Document 2: Handbook of Experimental Pharmacology,    Germany, Springer-Verlag, 2009, Vol. 191, p. 277-308-   Non Patent Document 3: The Journal of Clinical Investigation, USA,    American Society for Clinical Investigation, 2004, Vol. 113, p.    352-354-   Non Patent Document 4: The Journal of Clinical Investigation, USA,    American Society for Clinical Investigation, 2006, Vol. 116, p.    2552-2561-   Non Patent Document 5: European Respiratory Journal, Switzerland,    European Respiratory Society, 2008, Vol. 32, p. 881-891

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a novel compound whichhas a heme-independent activating function for soluble guanylate cyclaseand is useful as a pharmaceutical product.

Means for Solving the Problem

Under the circumstances, the inventors of the present inventionsynthesized various compounds and evaluated them using the solubleguanylate cyclase activating function as an indicator. As a result, itwas found that a compound having a structure that a bicyclic compoundconnected to a nitrogen atom has a high heme-independent property, anexcellent function of activating soluble guanylate cyclase, and isuseful as a pharmaceutical agent for prevention or treatment of variousdisorders that are related with soluble guanylate cyclase, and theinventors completed the present invention accordingly.

Specifically, the present invention is to provide a compound representedby General Formula (1), a pharmaceutically acceptable salt thereof, or asolvate thereof:

wherein A represents a C₁-C₃ linear alkylene group, wherein onemethylene group is optionally substituted with O or S;n represents an integer of from 3 to 5;X¹ and X² each independently represent CH or N;W¹ and W² each independently represent a carboxyl group or a tetrazolylgroup;V represents a C₁-C₈ linear or branched alkylene group, in which onemethylene group is optionally substituted with O or S;R represents a group selected from the followings:

in which R¹, R², R³, R⁴ and R⁵ represent a hydrogen atom, a halogenatom, a C₁-C₆ alkyl group which may have a substituent group, a C₁-C₆alkoxy group, a C₃-C₆ cycloalkyl group, a C₃-C₆ cycloalkoxy group, ahalo C₁-C₄ alkyl group, a halo C₁-C₄ alkoxy group, a vinyl group whichmay have a substituent group, an ethynyl group which may have asubstituent group, an aryl group which may have a substituent group onan aromatic ring, an aryloxy group which may have a substituent group onan aromatic ring, a benzyl group which may have a substituent group on abenzene ring, a phenethyl group which may have a substituent group on abenzene ring, a benzyloxy group which may have a substituent group on abenzene ring, a benzylsulfanyl group which may have a substituent groupon a benzene ring, a benzylamino group which may have a substituentgroup on a benzene ring, a phenyloxymethyl group which may have asubstituent group on a benzene ring, a phenylsulfanylmethyl group whichmay have a substituent group on a benzene ring, or a phenylaminomethylgroup which may have a substituent group on a benzene ring,m represents an integer of 1 or 2, andY¹ and Y² each independently represent methylene, O or S, with theproviso that both of them do not simultaneously represent S).

The present invention further provides a pharmaceutical agent containingthe compound represented by General Formula (1) shown above, apharmaceutically acceptable salt thereof, or a solvate thereof.

The present invention further provides a pharmaceutical compositioncontaining the compound represented by General Formula (1) shown above,a pharmaceutically acceptable salt thereof, or a solvate thereof, and apharmaceutically acceptable carrier.

The present invention further provides the compound represented byGeneral Formula (1) shown above, a pharmaceutically acceptable saltthereof, or a solvate thereof for prevention or treatment of disordersrelated with soluble guanylate cyclase such as heart failure,hypertension, pulmonary hypertension, or ischemic heart disease.

The present invention further provides a use of the compound representedby General Formula (1) shown above, a pharmaceutically acceptable saltthereof, or a solvate thereof for producing a pharmaceutical agent forprevention or treatment of disorders related with soluble guanylatecyclase such as heart failure, hypertension, pulmonary hypertension, orischemic heart disease.

The present invention still further provides a method for prevention ortreatment of disorders related with soluble guanylate cyclase such asheart failure, hypertension, pulmonary hypertension, or ischemic heartdisease, characterized in that an effective amount of the compoundrepresented by General Formula (1) shown above, a pharmaceuticallyacceptable salt thereof, or a solvate thereof is administered.

Advantageous Effects of the Invention

The compound of the present invention has a high heme-independentproperty, an excellent function of activating soluble guanylate cyclase,and is useful as a pharmaceutical agent for prevention or treatment ofvarious disorders related with soluble guanylate cyclase. Examples ofthe disorders that can be prevented or treated by the function ofactivating soluble guanylate cyclase include heart failure,hypertension, pulmonary hypertension, and ischemic heart disease.

DETAILED DESCRIPTION OF THE INVENTION

As described herein, the “linear alkylene group” indicates a linearalkylene group having a predetermined number of carbon atoms. Specificexamples thereof include a methylene group, —(CH₂)₂—, —(CH₂)₃—,—(CH₂)₄—, —(CH₂)₅—, and —(CH₂)₆—.

As described herein, the “branched alkylene group” indicates a branchedalkylene group having a predetermined number of carbon atoms. Specificexamples thereof include —CH(CH₃)—, —CH(C₂H₅)—, —CH(C₃H₇)—, —CH(C₄H₉)—,—CH(C₅H₁₁)—, —CH₂CH(CH₃)—, and —CH₂CH₂CH(CH₃)—.

As described herein, “one methylene group is optionally substituted withO or S” for the “linear or branched alkylene group” means that anymethylene group in the linear or branched alkylene group is substitutedwith O or S. Examples of a case in which the “linear alkylene group” isa methylene group with one carbon atom also include —O— and —S—.Specific examples thereof include —CH₂O—, —CH₂S—, —(CH₂)₂S—, —(CH₂)₃O—,—(CH₂)₃S—, —(CH₃)O—, —CH(CH₃)O—, —CH(CH₃)S—, —CH₂CH(CH₃)O—, and—CH₂CH(CH₃)S—.

As described herein, the “halogen atom” includes a fluorine atom, achlorine atom, a bromine atom, and an iodine atom.

As described herein, the “C₁-C₆ alkyl group” indicates a linear alkylgroup having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6carbon atoms. Examples of the C₁-C₆ alkyl group include a methyl group,an ethyl group, an n-propyl group, an n-butyl group, an isopropyl group,an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentylgroup, and an n-hexyl group.

As described herein, the “C₁-C₆ alkoxy group” indicates a group of the“C₁-C₆ alkyl group” in which one hydrogen atom is substituted with anoxygen atom. Specifically, it is a linear alkoxy group having 1 to 6carbon atoms or a branched alkoxy group having 3 to 6 carbon atoms, andexamples of the C₁-C₆ alkoxy group include a methoxy group, an ethoxygroup, an n-propoxy group, an isopropoxy group, an n-butoxy group, anisobutoxy group, a tert-butoxy group, an n-pentyloxy group, and ann-hexyloxy group.

As described herein, the “C₃-C₆ cycloalkyl group” indicates a cyclicalkyl group having 3 to 6 carbon atoms. Specific examples thereofinclude a cyclopropyl group, a cyclobutyl group, a cyclopentyl group,and a cyclohexyl group.

As described herein, the “C₃-C₆ cycloalkoxy group” indicates a group ofthe “C₃-C₆ cycloalkyl group” in which one hydrogen atom is substitutedwith an oxygen atom. Specific examples thereof include a cyclopropoxygroup, a cyclobutoxy group, a cyclopentyloxy group, and a cyclohexyloxygroup.

As described herein, the “halo C₁-C₄ alkyl group” indicates a group ofC₁-C₄ alkyl group, which is a linear alkyl group having 1 to 4 carbonatoms or a branched alkyl group having 3 or 4 carbon atoms, in which oneor more hydrogen atoms are substituted with a halogen atom. Examples ofthe halo C₁-C₄ alkyl group include a chloromethyl group, adichloromethyl group, a trichloromethyl group, a fluoromethyl group, adifluoromethyl group, a trifluoromethyl group, a bromomethyl group, adibromomethyl group, a tribromomethyl group, a 2-chloroethyl group, a2,2-dichloroethyl group, a 2,2,2-trichloroethyl group, a 2-fluoroethylgroup, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 1,1,22-tetrafluoroethyl group, a pentafluoroethyl group, a 2-bromoethylgroup, a 2,2,2-tribromoethyl group, a 3,3,3-trichloropropyl group, a3,3,3-trifluoropropyl group, a 3,3,3-tribromopropyl group, a4,4,4-trichlorobutyl group, and a 4,4,4-trifluorobutyl group.

As described herein, the “halo C₁-C₄ alkoxy group” indicates a group ofthe “halo C₁-C₄ alkyl group” in which one hydrogen atom is substitutedwith an oxygen atom. Examples of the halo C₁-C₄ alkoxy group include achloromethoxy group, a dichloromethoxy group, a trichloromethoxy group,a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxygroup, a 2-chloroethoxy group, a 2,2-dichloroethoxy group, a2,2,2-trichloroethoxy group, a 2-fluoroethoxy group, a2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a1,1,2,2-tetrafluoroethoxy group, a pentafluoroethoxy group, a3,3,3-trichloropropoxy group, a 3,3,3-trifluoropropoxy group, a4,4,4-trichlorobutoxy group, and a 4,4,4-trifluorobutoxy group.

As described herein, the “aryl group” indicates a monocyclic orpolycyclic aromatic hydrocarbon group having 6 to 10 carbon atoms.Examples of the aryl group include a phenyl group and a naphthyl group.More specific examples include a phenyl group, a 1-naphthyl group, and a2-naphthyl group.

As described herein, the “aryloxy group” indicates a group of the “arylgroup” in which one hydrogen atom is substituted with an oxygen atom.Examples of the aryloxy group include a phenoxy group and a naphthoxygroup. More specific examples include a phenoxy group, a 1-naphthoxygroup, and a 2-naphthoxy group.

As described herein, “which may have a substituent group” indicatesnon-substitution or having, on a substitutable position, one or moresubstituent groups that are the same with or different from each other,preferably 1 to 2, and more preferably one substituent group. Examplesof the substituent group include a halogen atom, a C₁-C₆ alkyl group, aC₁-C₆ alkoxy group, a C₃-C₅ cycloalkyl group, a C₃-C₆ cycloalkoxy group,a halo C₁-C₄ alkyl group, and an aryl group. Definition of eachsubstituent group is as defined above, and it may further have asubstituent group.

As for the halogen atom represented by R¹, R², R³, R⁴ and R⁵, it ispreferably a fluorine atom or a chlorine atom, and more preferably achlorine atom.

When the a C₁-C₆ alkyl group which may have a substituent group, whichis represented by R¹, R², R³, R⁴ and R⁵, has a substituent group,examples of the substituent group include a C₁-C₆ alkoxy group, a C₃-C₆cycloalkyl group, and a C₃-C₆ cycloalkoxy group. Among them, a C₃-C₆cycloalkyl group is preferable, and a cyclohexyl group is particularlypreferable. As for the C₁-C₆ alkyl group which may have a substituentgroup, it is preferably a methyl group, an ethyl group, an isopropylgroup, a tert-butyl group, a 2-methoxyethyl group, a 2-cyclopropylethylgroup, or a 2-cyclohexylethyl group, and more preferably an isopropylgroup, a tert-butyl group, or a 2-cyclohexylethyl group.

As for the C₁-C₆ alkoxy group represented by R¹, R², R³, R⁴ and R⁵, itis preferably a methoxy group, an ethoxy group, an n-propoxy group, anisopropoxy group, or a tert-butoxy group, and more preferably a methoxygroup or a tert-butoxy group.

As for the C₃-C₆ cycloalkyl group represented by R¹, R², R³, R⁴ and R⁵,it is preferably a cyclopropyl group or a cyclohexyl group, and morepreferably a cyclopropyl group.

As for the C₃-C₆ cycloalkoxy group represented by R¹, R², R³, R⁴ and R⁵,examples include a cyclopropyloxy group, a cyclopentyloxy group, and acyclohexyloxy group. It is preferably a cyclohexyloxy group.

As for the halo C₁-C₄ alkyl group represented by R¹, R², R³, R⁴ and R⁵,it is preferably a C₁-C₄ alkyl group substituted with one or morefluorine atoms. It is more preferably a C₁-C₄ alkyl group substitutedwith 1 to 5 fluorine atoms. Specific examples thereof include atrifluoromethyl group, a 2,2,2-trifluoroethyl group, a1,1,2,2-tetrafluoroethyl group, and a pentafluoroethyl group. Morepreferably, it is a trifluoromethyl group.

As for the halo C₁-C₄ alkoxy group represented by R¹, R², R³, R⁴ and R⁵,it is preferably a C₁-C₄ alkoxy group which is substituted with one ormore fluorine atoms. It is more preferably a C₁-C₄ alkoxy groupsubstituted with 1 to 5 fluorine atoms. Specific examples thereofinclude a trifluoromethoxy group, a 2,2,2-trifluoroethoxy group, a1,1,2,2-tetrafluoroethoxy group, and a pentafluoroethoxy group. Morepreferably, it is a trifluoromethoxy group.

When the vinyl group which may have a substituent group or the ethynylgroup which may have a substituent group, as represented by R², R², R³,R⁴ and R⁵, has a substituent group, the substituent group is preferablya C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, or an aryl group, and thearyl group is preferably a phenyl group. The aryl group may further havea substituent group such as a halogen atom, a C₁-C₆ alkyl group, or ahalo C₁-C₄ alkyl group. It is preferable that the vinyl group be notsubstituted or have 1 to 2 substituent groups. It is particularlypreferable for the vinyl group to have one substituent group. It ispreferable for the ethynyl group to have no substituent group or onesubstituent group. Examples of the vinyl group which may have asubstituent group or the ethynyl group which may have a substituentgroup include a vinyl group, a cyclohexylvinyl group, a styryl group, anethynyl group, a 3-methyl-1-butyn-1-yl group, a cyclopropylethynylgroup, a cyclohexylethynyl group, and a phenylethynyl group. It ispreferably a cyclohexylvinyl group, a styryl group, or acyclohexylethynyl group.

With regard to the aryl group which may have a substituent group on anaromatic ring or the aryloxy group which may have a substituent group onan aromatic ring, which is represented by R¹, R², R³, R⁴ and R⁵, thearomatic ring is preferably a benzene ring. When the aromatic ring has asubstituent group, the substituent group is preferably a halogen atom, aC₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a halo C₁-C₄ alkyl group. Itis preferable that the aryl group or aryloxy group which may have asubstituent group have no substituent group or 1 to 2 substituentgroups. It is more preferable that it have one substituent group at paraposition. Specific examples of the aryl group or aryloxy group which mayhave a substituent group include a phenyl group, a4-trifluoromethylphenyl group, a 4-chlorophenyl group, a4-tert-butylphenyl group, a 4-methoxyphenyl group, a phenoxy group, a4-trifluoromethylphenoxy group, a 4-chlorophenoxy group, a4-tert-butylphenoxy group, and a 4-methoxyphenoxy group. It is morepreferably a phenyl group, a 4-trifluoromethylphenyl group, a4-tert-butylphenyl group, a phenoxy group, a 4-trifluoromethylphenoxygroup, or a 4-tert-butylphenoxy group.

With regard to the benzyl group which may have a substituent group on abenzene ring, the phenethyl group which may have a substituent group ona benzene ring, the benzyloxy group which may have a substituent groupon a benzene ring, the benzylsulfanyl group which may have a substituentgroup on a benzene ring, the benzylamino group which may have asubstituent group on a benzene ring, the phenyloxymethyl group which mayhave a substituent group on a benzene ring, the phenylsulfanylmethylgroup which may have a substituent group on a benzene ring, or thephenylaminomethyl group which may have a substituent group on a benzenering, which is represented by R¹, R², R³, R⁴ and R⁵ (hereinbelow, thebenzyl group to the phenylaminomethyl group are collectively referred toas a type of the benzyl group), it is preferable that it be notsubstituted or have 1 to 2 substituent groups on a benzene ring. It isparticularly preferable that it have one substituent group at paraposition. As for the substituent group, it is preferably a halogen atom,a C₁-C₆ alkyl group, or a halo C₁-C₄ alkyl group, more preferably a haloC₁-C₄ alkyl group, and most preferably a trifluoromethyl group. As forthe type of benzyl group, it is preferably a phenethyl group, abenzyloxy group, or a benzylsulfanyl group, and particularly preferablya phenethyl group. Specific examples of the type of benzyl group whichmay have a substituent group on a benzene ring include a benzyl group, aphenethyl group, a benzyloxy group, a benzylsulfanyl group, abenzylamino group, a phenyloxymethyl group, a phenylsulfanylmethylgroup, a phenylaminomethyl group, a (4-fluoro)phenethyl group, a(4-fluoro)benzyloxy group, a (4-fluoro)benzylsulfanyl group, a(4-trifluoromethyl)phenethyl group, a (4-trifluoromethyl)benzyloxygroup, a (4-trifluoromethyl)benzylsulfanyl group, a(4-tert-butyl)phenethyl group, a (4-tert-butyl)benzyloxy group, and a(4-tert-butyl)benzylsulfanyl group. It is preferably a phenethyl group,a benzyloxy group, a benzylsulfanyl group, a phenyloxymethyl group, aphenylsulfanylmethyl group, or a phenylaminomethyl group, and morepreferably a phenethyl group, a benzyloxy group, or a benzylsulfanylgroup.

Specific examples of the C₁-C₃ linear alkylene group represented by Ainclude a methylene group, —O—, —S—, —CH₂CH₂—, —CH₂O—, —CH₂S—, —OCH₂—,—SCH₂—, —(CH₂)₃—, —OCH₂CH₂—, —SCH₂CH₂—, —CH₂OCH₂—, —CH₂SCH₂—, —CH₂CH₂O—,and —CH₂CH₂S—. Among them, a methylene group, —O—, —CH₂CH₂—, —CH₂O—,—OCH₂—, —CH₂CH₂CH₂—, —CH₂OCH₂—, —CH₂SCH₂—, and —CH₂CH₂O— are preferable,and —CH₂CH₂— and —CH₂O— are particularly preferable.

n is most preferably 4.

X² is most preferably CH.

W¹ and W² are preferably a carboxyl group.

Specific examples of the C₁-C₈ linear or branched alkylene grouprepresented by V include a methylene group, —O—, —S—, —CH₂CH₂—,—CH(CH₃)O—, —CH₂CH(CH₃)—, —CH₂CH(CH₃)O—, —CH₂CH(CH₃)S—, —CH₂O—, —CH₂S—,—OCH₂—, and —SCH₂—. Among them, —CH₂CH₂—, —CH(CH₃)O—, and —CH₂O— arepreferable, and —CH₂O— is particularly preferable.

When the group represented by R corresponds to the following formula,

wherein m represents an integer of 1 or 2, andY¹ and Y² each independently represent a methylene group, O, or S, withthe proviso that it is not simultaneously S)specific examples thereof include a group represented by the followingformula.

Among them, a group selected from the following formula is preferable.

As for the group represented by R, a group selected from the followingformula

is preferable, and

the above are particularly preferable.

As for R¹, a C₁-C₆ alkyl group which may have a substituent group, aC₃-C₆ cycloalkyl group, a C₁-C₆ alkoxy group, a halo C₁-C₄ alkyl group,a vinyl group which may have a substituent group, an ethynyl group whichmay have a substituent group, an aryl group which may have a substituentgroup on an aromatic ring, an aryloxy group which may have a substituentgroup on an aromatic ring, a benzyl group which may have a substituentgroup on a benzene ring, a phenethyl group which may have a substituentgroup on a benzene ring, a benzyloxy group which may have a substituentgroup on a benzene ring, a benzylsulfanyl group which may have asubstituent group on a benzene ring, a benzylamino group which may havea substituent group on a benzene ring, a phenyloxymethyl group which mayhave a substituent group on a benzene ring, a phenylsulfanylmethyl groupwhich may have a substituent group on a benzene ring, or aphenylaminomethyl group which may have a substituent group on a benzenering is preferable. More preferably, it is a C₁-C₆ alkyl group, a C₃-C₆cycloalkyl group, a vinyl group which may have a substituent group, anethynyl group which may have a substituent group, a phenethyl groupwhich may have a substituent group on a benzene ring, a benzyloxy groupwhich may have a substituent group on a benzene ring, or abenzylsulfanyl group which may have a substituent group on a benzenering. Position for R² substitution is preferably meta position or paraposition. Herein, the substituent group on the C₁-C₆ alkyl group ispreferably a C₁-C₆ alkoxy group, a C₃-C₆ cycloalkyl group, or a C₃-C₆cycloalkoxy group. The substituent group on the vinyl group or theethynyl group is preferably a C₁-C₆ alkyl group, a C₃-C₆ cycloalkylgroup, a phenyl group, a halogenophenyl group, a C₁-C₆ alkylphenylgroup, or a halo C₁-C₄ alkylphenyl group. As for the aryl group, aphenyl group is preferable. As for the aryloxy group, a phenoxy group ispreferable. The substituent group on the aryl or aryloxy group ispreferably a halogen atom, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, ora halo C₁-C₄ alkyl group. The substituent group on the benzene ring ispreferably a halogen atom, a C₁-C₆ alkyl group, or a halo C₁-C₄ alkylgroup.

As for R², a vinyl group which may have a substituent group, an ethynylgroup which may have a substituent group, a benzyl group which may havea substituent group on a benzene ring, a phenethyl group which may havea substituent group on a benzene ring, a benzyloxy group which may havea substituent group on a benzene ring, a benzylsulfanyl group which mayhave a substituent group on a benzene ring, a benzylamino group whichmay have a substituent group on a benzene ring, a phenyloxymethyl groupwhich may have a substituent group on a benzene ring, aphenylsulfanylmethyl group which may have a substituent group on abenzene ring, or a phenylaminomethyl group which may have a substituentgroup on a benzene ring is preferable. More preferably, it is a vinylgroup which may have a substituent group, a phenethyl group which mayhave a substituent group on a benzene ring, a benzyloxy group which mayhave a substituent group on a benzene ring, or a benzylsulfanyl groupwhich may have a substituent group on a benzene ring. Most preferably,it is a phenethyl group which may have a substituent group on a benzenering. Herein, the substituent group on the vinyl group or the ethynylgroup is preferably a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, aphenyl group, a halogenophenyl group, a C₁-C₆ alkylphenyl group, or ahalo C₁-C₄ alkylphenyl group. The substituent group on a benzene ring ispreferably a halogen atom, a C₁-C₆ alkyl group, or a halo C₁-C₄ alkylgroup.

As for R³, a hydrogen atom, a C₁-C₆ alkyl group which may have asubstituent group, a C₁-C₆ alkoxy group, or a halo C₁-C₄ alkyl group, ispreferable. Most preferably, it is a hydrogen atom. Position for R³substitution is most preferably para position. Herein, the substituentgroup on the C₁-C₆ alkyl group is preferably a C₁-C₆ alkoxy group, aC₃-C₆ cycloalkyl group, or a C₃-C₆ cycloalkoxy group.

As for R⁴, a hydrogen atom, a C₁-C₆ alkyl group which may have asubstituent group, a C₁-C₆ alkoxy group, or a halo C₁-C₄ alkyl group, anaryl group which may have a substituent group on an aromatic ring, or anaryloxy group which may have a substituent group on an aromatic ring ispreferable. Most preferably, it is a hydrogen atom. Position for R⁴substitution is preferably 6 position. Herein, the substituent group onthe C₁-C₆ alkyl group is preferably a C₁-C₆ alkoxy group, a C₃-C₆cycloalkyl group, or a C₃-C₆ cycloalkoxy group. As for the aryl group, aphenyl group is preferable. As for the aryloxy group, a phenoxy group ispreferable. The substituent group on the aryl or aryloxy group ispreferably a halogen atom, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, ora halo C₁-C₄ alkyl group.

As for R⁵, a hydrogen atom, a benzyl group which may have a substituentgroup on a benzene ring, a phenethyl group which may have a substituentgroup on a benzene ring, a benzyloxy group which may have a substituentgroup on a benzene ring, a benzylsulfanyl group which may have asubstituent group on a benzene ring, a benzylamino group which may havea substituent group on a benzene ring, a phenyloxymethyl group which mayhave a substituent group on a benzene ring, a phenylsulfanylmethyl groupwhich may have a substituent group on a benzene ring, or aphenylaminomethyl group which may have a substituent group on a benzenering is preferable. It is more preferably a hydrogen atom or a phenethylgroup. Position for R⁵ substitution is preferably 6 position. Herein,the substituent group on a benzene ring is preferably a halogen atom, aC₁-C₆ alkyl group, or a halo C₁-C₄ alkyl group.

In General Formula (1), it is preferable that A be a methylene group,—O—, —CH₂CH₂—, —CH₂O—, —OCH₂—, —CH₂CH₂CH₂—, —CH₂OCH₂—, —CH₂SCH₂— or—CH₂CH₂O—;

n be an integer of from 3 to 5;

W¹ and W² be a carboxy group;

V be —CH₂CH₂—, —CH(CH₃)O— or —CH₂O—; and

R be as follows:

In the formula, R¹, R², Y¹, Y² and m are as defined above.

In General Formula (1), it is more preferable that A be a methylenegroup, —O—, —CH₂CH₂—, —CH₂O—, —OCH₂—, —CH₂CH₂CH₂—, —CH₂OCH₂—, —CH₂SCH₂—or —CH₂CH₂O;

n be an integer of 4;

W¹ and W² be a carboxyl group.

V be —CH₂CH₂—, —CH(CH₃)O— or —CH₂O—; and

R be as follows:

In the formula, R¹, R², Y¹, Y² and m are as defined above.

In the preferred embodiment, R¹ is preferably a C₁-C₆ alkyl group whichmay have a substituent group, a C₃-C₆ cycloalkyl group, a C₁-C₆ alkoxygroup, a halo C₁-C₄ alkyl group, a vinyl group which may have asubstituent group, an ethynyl group which may have a substituent group,an aryl group which may have a substituent group on an aromatic ring, anaryloxy group which may have a substituent group on an aromatic ring, abenzyl group which may have a substituent group on a benzene ring, aphenethyl group which may have a substituent group on a benzene ring, abenzyloxy group which may have a substituent group on a benzene ring, abenzylsulfanyl group which may have a substituent group on a benzenering, a benzylamino group which may have a substituent group on abenzene ring, a phenyloxymethyl group which may have a substituent groupon a benzene ring, a phenylsulfanylmethyl group which may have asubstituent group on a benzene ring, or a phenylaminomethyl group whichmay have a substituent group on a benzene ring. More preferably, it is aC₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, a vinyl group which mayhave a substituent group, an ethynyl group which may have a substituentgroup, a phenethyl group which may have a substituent group on a benzenering, a benzyloxy group which may have a substituent group on a benzenering, or a benzylsulfanyl group which may have a substituent group on abenzene ring. Herein, the substituent group on an alkyl group, a vinylgroup, an ethynyl group, an aryl group, an aryloxy group, and a benzenering is preferably the same as those described above.

As for R², a vinyl group which may have a substituent group, an ethynylgroup which may have a substituent group, a benzyl group which may havea substituent group on a benzene ring, a phenethyl group which may havea substituent group on a benzene ring, a benzyloxy group which may havea substituent group on a benzene ring, a benzylsulfanyl group which mayhave a substituent group on a benzene ring, a benzylamino group whichmay have a substituent group on a benzene ring, a phenyloxymethyl groupwhich may have a substituent group on a benzene ring, aphenylsulfanylmethyl group which may have a substituent group on abenzene ring, or a phenylaminomethyl group which may have a substituentgroup on a benzene ring is preferable. More preferably, it is a vinylgroup which may have a substituent group, a phenethyl group which mayhave a substituent group on a benzene ring, a benzyloxy group which mayhave a substituent group on a benzene ring, or a benzylsulfanyl groupwhich may have a substituent group on a benzene ring. Most preferably,it is a phenethyl group which may have a substituent group on a benzenering. Herein, the substituent group on a vinyl group, an ethynyl group,and a benzene ring is preferably the same as those described above.

In the preferred embodiment,

when R is as shown above,

it is preferably a group selected from above.

Specific examples of the particularly preferred compounds among thecompounds of General Formula (1) of the present invention include thefollowings.

-   1-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}indane-5-carboxylic    acid (Example 1)-   5-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 2)-   5-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic    acid (Example 3)-   4-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}chromane-7-carboxylic    acid (Example 4)-   4-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}thiochromane-7-carboxylic    acid (Example 5)-   5-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic    acid (Example 6)-   3-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-2,3-dihydrobenzofuran-6-carboxylic    acid (Example 7)-   4-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-isochromane-7-carboxylic    acid (Example 8)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(2-chlorobenzyloxyl)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 13)-   5-{N-[2-[2-(4-Benzyloxybenzyloxyl)phenyl]ethyl]-N-(4-carboxybutyl)amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 14)-   5-{N-[2-[2-(4-Benzylsulfanylbenzyloxyl)phenyl]ethyl]-N-(4-carboxybutyl)amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 15)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(4-phenoxymethylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 16)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(4-phenylsulfanylmethylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 17)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(4-ethynylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 19)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(4-cyclohexylethynylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 22)-   5-{N-(4-Carboxybutyl)-N-[2-[2-[4-((E)-2-cyclohexylethenyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 23)-   5-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-cyclohexylethyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 24)-   5-{N-(4-Carboxybutyl)-N-[2-[2-[trans-4-(2-phenylethyl)cyclohexylmethoxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 26)-   5-{N-(4-Carboxybutyl)-N-[2-[2-[cis-4-(2-phenylethyl)cyclohexylmethoxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 27)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(5,6,7,8-tetrahydronaphthalene-1-ylmethoxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 29)-   5-{N-[2-[2-(3-tert-Butylbenzyloxy)phenyl]ethyl]-N-(4-carboxybutyl)amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 41)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(4-cyclopropylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 42)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(4-isopropylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 43)-   5-{N-[2-[2-[(1R)-1-(4-tert-Butylphenyl)ethoxy]phenyl]ethyl]-N-(4-carboxybutyl)amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 45)-   5-{N-(4-Carboxybutyl)-N-[2-[2-(indane-5-ylmethoxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylic    acid (Example 46)

As described herein, the compound of General Formula (1) may yield anisomer such as geometric isomer, optical isomer, stereo isomer, ortautomeric isomer. The compounds of General Formula (1) of the presentinvention include any one of those isomers or a mixture of them.

Furthermore, the compound of General Formula (1) of the presentinvention includes compounds obtained by labeling with, for example, anisotope (for example, ²H, ³H, ¹⁴C, ³⁵C, ³⁵S or ¹²⁵I).

Furthermore, the present invention includes pharmaceutically acceptablesalts of the compound of General Formula (1). Specific examples thereofinclude acid addition salts with inorganic acids, such as hydrochloride,hydrobromide, hydroiodide, sulfate, nitrate and phosphate, acid additionsalts with organic acids, such as formate, acetate, trichioroacetate,trifluoroacetate, propionate, oxalate, malonate, succinate, fumarate,maleate, lactate, malate, tartrate, citrate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate(4-methylbenzenesulfonate), asparaginate and glutamate; salts withinorganic bases, such as sodium salts, potassium salts, magnesium salts,calcium salts, ammonium salts, and aluminum salts; and salts withorganic bases, such as methylamine, ethylamine, ethanolamine, lysine,and ornithine.

Furthermore, according to the present invention, hydrates, varioussolvates and crystal polymorphisms of the compound (1) of the presentinvention and pharmaceutically acceptable salts thereof may exist.However, similarly, there are no limitations, and the present inventionmay include any single crystal form and a mixture of crystal forms andmay include any of them.

Furthermore, the compound (1) of the present invention may be preparedas a prodrug by having a pharmaceutically acceptable group. Examples ofthe pharmaceutically acceptable group that forms a prodrug include thegroups described in Prog. Med., 5, 2157-2161 (1985), or “Development ofPharmaceutical Products” (Hirokawa Shoten Ltd., 1990) Vol. 7, MolecularDesign, 163-198.

The compound of General Formula (1) of the present invention, apharmaceutically acceptable salt, or a solvate thereof (hereinbelow,they are collectively referred to as the compound of the presentinvention) can be produced by utilizing the features based on the typeof the basic skeleton or a substituent group thereof, and applyingvarious synthesis methods that are known per se in connection with theintroduction of substituent groups or conversion of functional groups.

Examples of the method for producing the compound of the presentinvention are given below, however, the production method for thecompound of the present invention is not intended to be limited to thesemethods.

The compound of General Formula (1) can be produced according to thefollowing scheme, for example.

wherein A, n, X¹, X², W¹, W², R and V are as defined above. U¹ and U²each correspond to W¹ and W², and when W¹ and/or W² is a tetrazolylgroup, U¹ and/or U² is a cyano group and when W¹ and/or W² is a carboxylgroup, U¹ and/or U² represents CO₂R⁶. Q¹ and Q² each correspond to W¹and W², and when W¹ and/or W² is a tetrazolyl group, Q¹ and/or Q² isalso a tetrazolyl group and when W¹ and/or W² is a carboxyl group, Q¹and/or Q² represents CO₂R⁶. Herein, R⁶ represents a C₁-C₆ alkyl group. Erepresents a leaving group or a hydroxyl group).

As described herein, the “leaving group” represents a group which issubstituted in the presence of a base or a group having an activatedoxygen atom. Specific examples thereof include a halogen atom; atrihalogenomethyloxy group such as a trichloromethyloxy; a lower alkanesulfonyloxy group such as a methanesulfonyloxy group or anethanesulfonyloxy group; a lower halogenoalkane sulfonyloxy group suchas a trifluoromethanesulfonyloxy group or a pentafluoroethanesulfonyloxygroup; and an arylsufonyloxyl group such as a benzenesulfonyloxy group,a p-toluenesulfonyloxy group, or a p-nitrobenzenesulfonyloxy group.

Step 1: Nosyl protection

The compound (3) can be produced by reacting the compound (2) with anagent for introducing a nitrobenzenesulfonyl group in the presence orabsence of a base, in the absence of a solvent or in an inert solvent.Examples of the agent for introducing a nitrobenzenesulfonyl group whichcan be used include 2-nitrobenzenesulfonyl chloride and4-nitrobenzenesulfonyl chloride. The use amount of the agent forintroducing a nitrobenzenesulfonyl group is, with respect to thecompound (2), generally 1 to 5 equivalents, and preferably 1 to 2equivalents. Examples of the base which can be used include alkali metalcarbonate salt, alkali metal hydrogen carbonate salt, alkali metalhydroxide, and tertiary organic amines such as triethylamine ordiisopropylethylamine. Examples of the solvent which can be used includearomatic hydrocarbons such as benzene or toluene, nitriles such asacetonitrile, propionotirile, or butyronitrile, halogenated hydrocarbonssuch as chloroform or dichloromethane, ethers such as diethyl ether ortetrahydrofuran (hereinbelow, referred to as THF), water, or a mixturethereof. The reaction temperature is usually −30° C. to 40° C., andpreferably 0° C. to room temperature. The reaction time is usually 0.5to 24 hours, and preferably 0.5 to 3 hours.

Meanwhile, the compound (2) is either commercially available or can beproduced by a known method.

Step 2: Mitsunobu Reaction

The compound (5) can be produced by reacting the compound (3) and thecompound (4) in the presence of a dehydration and condensation agent,and in the absence of a solvent, or in an inert solvent.

The use amount of the compound (4) is, with respect to the compound (3),generally 1 to 3 equivalents, and preferably 1 to 1.5 equivalents.Examples of the dehydration and condensation agent which can be usedinclude a combination of an azodicarboxylic acid compound such asdiethyl azodicarboxylate or 1,1′-azobis(N,N-dimethyl formamide) andphosphines such as triphenyl phosphine or tri-n-butyl phosphine. The useamount of the dehydration and condensation agent is, with respect to thecompound (3), generally 1 to 3 equivalents, and preferably 1 to 1.5equivalents for each. Examples of the solvent which can be used includearomatic hydrocarbons such as benzene or toluene, halogenatedhydrocarbons such as chloroform or dichloromethane, ethers such asdiethyl ether or THF, and amides such as N,N-dimethyl formamide(hereinbelow, referred to as DMF) or dimethyl acetamide. The reactiontemperature is usually −30° C. to 40° C., and preferably 0° C. to roomtemperature. The reaction time is usually 1 to 48 hours, and preferably1 to 24 hours.

Meanwhile, the compound (4) is either commercially available or can beproduced by a known method.

Step 3: Nosyl Deprotection Reaction

The compound (6) can be produced by reacting the compound (5) in thepresence of a base and a deprotecting agent, and in the absence of asolvent, or in an inert solvent.

The deprotecting agent which can be used is, for example, primary orsecondary organic amines such as n-propyl amine or pyrrolidine; andthiols such as 1-dodecane thiol, thiophenol, or thioglycolic acid. Theuse amount of the deprotecting agent is, with respect to the compound(5), generally 1 to 5 equivalents, and preferably 1 to 2 equivalents.Examples of the base which can be used include alkali metal carbonatesalt, alkali metal hydrogen carbonate salt, alkali metal hydride, alkalimetal alkoxide, and tertiary organic amines. Examples of the solventwhich can be used include nitriles such as acetonitrile, propionotirile,or butyronitrile, halogenated hydrocarbons such as chloroform ordichloromethane, amides such as DMF or dimethyl acetamide, or a mixturethereof. The reaction temperature is usually −30° C. to 40° C., andpreferably 0° C. to room temperature. The reaction time is usually 1 to48 hours, and preferably 1 to 24 hours.

Step 4: Alkylation

The compound (8) can be produced by reacting the compound (6) and thecompound (7) in the presence of a base, and if necessary with anadditive, in the absence of a solvent, or in an inert solvent. The useamount of the compound (7) is, with respect to the compound (6),generally 1 to 5 equivalents, and preferably 1 to 3 equivalents.Examples of the base which can be used include alkali metal carbonatesalt, alkali metal hydrogen carbonate salt, alkali metal hydride, alkalimetal alkoxide, and organic amines such as triethylamine,diisopropylethylamine, or pyridine. Examples of the additive which canbe used include a phase transfer catalyst such as alkali metal iodide,tetrabutylammonium salt, or crown ether. Examples of the solvent whichcan be used include aromatic hydrocarbons such as benzene or toluene,nitriles such as acetonitrile, propionotirile, or butyronitrile,halogenated hydrocarbons such as chloroform or dichloromethane, ketones,ethers such as diethyl ether or THF, alcohols such as methanol, ethanol,or 2-propanol, amides such as DMF or dimethyl acetamide, or a mixturethereof. The reaction temperature is usually room temperature to 150°C., and preferably room temperature to 100° C. The reaction time isusually 5 to 72 hours, and preferably 8 to 48 hours.

Step 5: Tetrazole cyclization

The compound (9) can be produced by, when at least one of U¹ and U² ofthe compound (8) is a cyano group, a known method for converting a cyanogroup to a tetrazolyl group, for example, a method of having thereaction in an inert solvent in the presence of an azide compound.

Examples of the azide compound which can be used include azide metalsalt, trialkyl tin azide, ammonium azide, and trimethylsilyl azide. Forthe present step, an additive may be suitably used, if necessary.Examples of the additive which can be used include aluminum chloride,quaternary ammonium salt, magnesium salt, dialkyl tin oxide, and zincchloride. Examples of the solvent which can be used include aromatichydrocarbons such as benzene or toluene, halogenated hydrocarbons suchas chloroform or dichloromethane, ethers such as diethyl ether or THF,amides such as DMF or dimethyl acetamide, or a mixture thereof. Thereaction temperature is usually room temperature to 180° C., andpreferably 50° C. to 120° C. The reaction time is usually 5 to 72 hours,and preferably 8 to 48 hours.

Step 6: Hydrolysis

The compound (1) of General Formula (1) can be produced by, when atleast one of Q¹ and Q² of the compound (9) is CO₂R⁶, performingde-esterification of the compound (9).

The de-esterification reaction can be performed typically by a methodwell known in the field of synthetic organic chemistry, depending on atype of ester group (CO₂R⁶). For example, by performing the hydrolysisreaction in the presence of a base, the compound of General Formula (1)can be produced.

Examples of the base which can be used include alkali metal carbonatesalt, alkali metal hydroxide, alkali earth metal hydroxide, and alkalimetal alkoxide. Examples of the solvent which can be used include etherssuch as diethyl ether or THF, alcohols such as methanol, ethanol, or2-propanol, water, or a mixture thereof. Meanwhile, for the presenthydrolysis reaction, water is essential. The reaction temperature isusually 0° C. to 150° C., and preferably room temperature to 80° C. Thereaction time is usually 1 to 48 hours, and preferably 3 to 24 hours.

Meanwhile, when both W¹ and W² in General Formula (1) are a carboxylgroup, Step 5 can be omitted. Further, when both W¹ and W² are atetrazolyl group, Step 6 can be omitted. Further, by performing ade-esterification reaction of the optically active compounds (8) and(9), the optically active compound of General Formula (1) can beproduced. Further, with regard to the compound of General Formula (1),the optically active compound of General Formula (1) can be alsoproduced via HPLC fractionation using a chiral column.

When V is —O—, —CH(CH₃)O—, or —CH₂O—, the compound of General Formula(1) can be produced by obtaining the compound (8) according to themethod of the scheme shown below from the compound (11), which isobtained from the compound (10) of the following formula according tothe same method as above Step 1 to Step 4

wherein R⁷ represents a protecting group for hydroxyl group).

wherein A, n, X¹, X², R, U¹, U², E and R⁷ are as defined above, V is—O—, —CH(CH₃)O— or —CH₂O—, and G is a single bond or a methylene group).Meanwhile, the compound (10) is either commercially available or can beproduced by a known method.

Step 7: Deprotection

The compound (12) can be produced by performing deprotection of thecompound (11).

The deprotection can be performed typically by a method well known inthe field of synthetic organic chemistry (for example, the methoddisclosed by T. W. Greene, P. G. Wuts, Greene's Protective Groups inOrganic Synthesis. Fourth Edition, 2006, John Wiley & Sons, Inc.).

Step 8: Alkylation and Mitsunobu reaction

When E in the compound (13) is a leaving group, the compound (8) can beproduced from the compound (12) and the compound (13) according to thesame method as Step 4 above.

Further, when E in the compound (13) is a hydroxyl group, the compound(8) can be produced from the compound (12) and the compound (13)according to the same method as Step 2 above.

Further, the compound of General Formula (1) can be also produced byobtaining the compound (6) according to the method of the followingscheme.

wherein A, X¹, X², R, V and U¹ are as defined above).

Step 9: Oxidation

The compound (15) can be produced by reacting the compound (14) and anoxidizing agent in an inert solvent.

Examples of the oxidizing agent which can be used include a hypervalentiodine compounds such as1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (DMP) or1-hydroxy-1,2-benziodoxol-3(1H)-one-1-oxide (IBX); combination ofaluminum alkoxide and a hydrogen acceptor such as benzoquinone,benzophenone, acetone, or benzaldehyde; combination oftetrapropylammonium perruthenate (TPAP) or2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) and a co-oxidizingagent such as hypochlorite, hypobromide, or N-chlorosuccinimide; andcombination of dimethyl sulfoxide (hereinbelow, referred to as DMSO) andan electrophilic activating reagent such as dicyclohexylcarbodiimide,phosphorus pentoxide, acetic anhydride, or oxalyl chloride. The useamount of the oxidizing agent is, with respect to the compound (14),generally 1 to 10 equivalents, and preferably 1 to 3 equivalents. Forthe present step, a base such as pyridine or sodium hydrogen carbonatecan be added, if necessary. Examples of the solvent which can be usedinclude aromatic hydrocarbons such as benzene or toluene, nitriles suchas acetonitrile, propionitrile, or butyronitrile, halogenatedhydrocarbons such as chloroform or dichloromethane, ethers such asdiethyl ether or THF, esters such as ethyl acetate, propyl acetate, orbutyl acetate, amides such as DMF or dimethyl acetamide, sulfoxides suchas DMSO or sulfolane, or a mixture thereof. The reaction temperature isusually −30° C. to 100° C., and preferably 0° C. to room temperature.The reaction time is usually 0.5 to 24 hours, and preferably 1 to 8hours.

Step 10: Reductive amination

The compound (6) can be produced by reacting the compound (15) and thecompound (16) in the presence or absence of an acid, and in the absenceof a solvent, or in an inert solvent to obtain first a Schiff basefollowed by reacting it in the presence of a reducing agent.

The use amount of the compound (16) is, with respect to the compound(15), generally 1 to 3 equivalents, and preferably 1 to 1.5 equivalents.Examples of the acid which can be used include inorganic acid such ashydrochloric acid, hydrobromic acid, phosphoric acid, or sulfuric acid,and an organic acid such as formic acid, acetic acid, propinonic acid,methane sulfonic acid, or p-toluene sulfonic acid. Examples of thereducing agent which can be used include a borohydride compound such asborane-tetrahydrofuran complex, sodium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride; an aluminum hydridecompound such as lithium aluminum hydride; and hydrogen. The use amountof the reducing agent is, with respect to the compound (15), generally 1to 10 equivalents, and preferably 1 to 5 equivalents. Examples of thesolvent which can be used include aromatic hydrocarbons such as benzeneor toluene, halogenated hydrocarbons such as chloroform ordichloromethane, ethers such as diethyl ether or THF, esters such asethyl acetate, propyl acetate, or butyl acetate, alcohols such asmethanol, ethanol, or 2-propanol, or a mixture thereof. The reactiontemperature is usually −78° C. to 150° C., and preferably 0° C. to 60°C. The reaction time is usually 5 minutes to 24 hours, and preferably 30minutes to 4 hours.

Meanwhile, the compound (16) is either commercially available or can beproduced by a known method.

The compound of the present invention which is obtained as describedabove has sGC activating function with excellent heme-independentproperty as shown in the following test examples. Thus, the compound ofthe present invention is useful as a pharmaceutical agent for preventionand treatment of disorders of an animal including human beings that arerelated with sGC, in particular, various disorders for which the sGCactivating function is effective. Examples of the disorders includeheart failure, hypertension, pulmonary hypertension, and ischemic heartdisease.

When the compound of the present invention is used as a pharmaceuticalagent, the administration can be made by either oral administration orparenteral administration. The dosage of the compound of the presentinvention is appropriately determined according to individual cases inconsideration of, for example, the disease or symptom to be treated, theage, body weight or gender of the subject of administration.Conventionally, in the case of oral administration, the dosage of thecompound of the present invention for an adult (body weight of about 60kg) per day is suitably 1 mg to 1000 mg, preferably 3 mg to 300 mg, andmore preferably 10 mg to 200 mg, and it is administered once or in 2 to4 divided doses. Furthermore, in the case of intravenous administration,the dosage for an adult per day is suitably 0.01 mg to 100 mg,preferably 0.01 mg to 50 mg, and more preferably 0.01 mg to 20 mg, perkilogram of the weight, and it is administered once or in multipledivided doses a day.

The pharmaceutical composition of the present invention can be preparedby a general method using at least one kind of the compound of thepresent invention and a pharmaceutically acceptable additive.

Examples of the pharmaceutical composition of the present invention fororal administration include a tablet, a pill, a capsule, a granule,powder, an emulsion, a solution, a suspension, a syrup, and an elixir.They can be generally prepared as a pharmaceutical composition in whichat least one kind of the compound of the present invention and anadditive such as pharmaceutically acceptable diluent, an excipient, or acarrier are admixed. It is also possible to contain an additive such asa binder, a disintegrating agent, a lubricating agent, a swelling agent,a swelling aid, a coating agent, a plasticizer, a stabilizing agent, ananti-septic agent, an anti-oxidizing agent, a coloring agent, adissolution aid, a suspension agent, an emulsifying agent, a sweeteningagent, a preservative, a buffer agent, or a wetting agent.

Examples of the pharmaceutical composition of the present invention forparenteral administration include an injection solution, a suppository,an eye drop, an inhaling agent, an ointment, a gel, a crème, and apatch. They can be generally prepared as a pharmaceutical composition inwhich at least one kind of the compound of the present invention and anadditive such as pharmaceutically acceptable diluent, auxiliary agent,or a carrier are admixed. It is also possible to contain an additivesuch a stabilizing agent, an anti-septic agent, a dissolution aid, amoisturizing agent, a preservative, an anti-oxidizing agent, a flavoringagent, a gelling agent, a neutralizing agent, a buffer agent, anisotonic agent, a surfactant, a coloring agent, a buffering agent, athickening agent, a wetting agent, a filling agent, an absorptionpromoter, a suspension agent, or a binder.

Further, as long as it is not against the purpose of the presentinvention, the pharmaceutical composition containing the compound of thepresent invention may suitably contain other kind of a pharmaceuticallyeffective component like diuretics.

Hereinbelow, the present invention is specifically described by way ofexamples, however, the present invention is not limited to them.

Reference Example 1 Methoxymethyl 2-(2-nitrovinyl)phenyl ether

2-Methoxymethoxybenzaldehyde (16.4 g) was suspended in nitromethane (54mL), added with ammonium acetate (5.95 g), and stirred for 30 minutes at80° C. After cooling to room temperature, the solvent was evaporatedunder reduced pressure and the residue was suspended in water and thenextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium hydrogen carbonate and saturatedbrine in order and dried over anhydrous sodium sulfate. The solvent wasthen evaporated under reduced pressure. The residues were purified bydiol silica gel column chromatography (5% ethyl acetate/hexane) toobtain the title compound (11.6 g) as a yellow oil.

¹H-NMR (CDCl₃) δ: 8.22 (1H, d, J=13.6 Hz), 7.83 (1H, d, J=13.6 Hz),7.50-7.41 (2H, m), 7.23 (1H, dd, J=8.4, 0.9 Hz), 7.07 (1H, ddd, J=8.4,7.5, 1.1 Hz), 5.33 (2H, s), 3.52 (3H, s).

Reference Example 2 2-(2-Methoxymethoxyphenyl)ethylamine

Lithium aluminum hydride (6.30 g) was suspended in tetrahydrofuran(hereinbelow, THF) (400 mL), added dropwise with a THF solution (100 mL)of Reference Example 1 (11.6 g) under ice cooling, and heated at refluxfor 30 minutes. Under ice cooling, sodium sulfate decahydrate (21.4 g)was added in small portions, stirred for 15 minutes at room temperature,and filtered through Celite. The solvent was evaporated under reducedpressure. The residues were purified by silica gel column chromatography(20% methanol/chloroform) to obtain the title compound (6.73 g) as ayellow oil.

¹H-NMR (CDCl₃) δ: 7.21-7.15 (2H, m), 7.09-7.06 (1H, m), 6.97-6.92 (1H,m), 5.21 (2H, s), 3.48 (3H, s), 2.95 (2H, t, J=6.9 Hz), 2.79 (2H, t,J=6.9 Hz).

Reference Example 3 Methyl 3-mercaptobenzoate

3-Mercaptobenzoic acid (10.0 g) was suspended in methanol (310 mL),added with sulfuric acid (0.3 mL), and stirred for 24 hours under refluxwith heating. After cooling to room temperature, the solvent wasevaporated under reduced pressure and water was added to residues. Afteradjusting to pH 8 by using a saturated aqueous solution of sodiumhydrogen carbonate, it was extracted with ethyl acetate and dried overanhydrous sodium sulfate. After distilling the solvent under reducedpressure, the residues were purified by silica gel column chromatography(10% ethyl acetate/hexane) to obtain the title compound as a colorlessoil.

¹H-NMR (CDCl₃) δ: 7.95 (1H, dd, J=2.0, 1.5 Hz), 7.82 (1H, ddd, J=7.7,1.5, 1.3 Hz), 7.45 (1H, ddd, J=7.9, 2.0, 1.3 Hz), 7.31 (1H, dd, J=7.9,7.7 Hz), 3.91 (3H, s), 3.54 (1H, s).

Reference Example 4 3-(3-Methoxycarbonylphenylsulfanyl)propionic acid

Reference Example 3 (10.3 g) was dissolved in acetone (150 mL), addedwith potassium carbonate (17.0 g) and 3-bromopropionic acid (10.3 g)under ice cooling, and stirred for 2.5 hours at room temperature. Thesolvent was evaporated under reduced pressure, and the residues weresuspended in water. After adjusting to pH 1 using 6 mol/L hydrochloricacid, it was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine in order and dried over anhydrous sodiumsulfate. The solvent was then evaporated under reduced pressure. Theresidues were purified by silica gel column chromatography (50% ethylacetate/hexane) to obtain the title compound (14.5 g) as a white powder.

¹H-NMR (CDCl₃) δ: 8.03 (1H, dd, J=1.8, 1.7 Hz), 7.88 (1H, ddd, J=7.9,1.7, 1.1 Hz), 7.55 (1H, ddd, J=7.7, 1.8, 1.1 Hz), 7.38 (1H, dd, J=7.9,7.7 Hz), 3.92 (3H, s), 3.22 (2H, t, J=7.3 Hz), 2.70 (2H, t, J=7.3 Hz).

Reference Example 5 Methyl 4-oxothiochromane-7-carboxylate

Reference Example 4 (2.40 g) was suspended in polyphosphoric acid (13mL) and stirred for 15 minutes at 70° C. After cooling to roomtemperature, ice and water were added thereto. After extraction withethyl acetate, the organic layer was washed with a saturated aqueoussolution of sodium hydrogen carbonate and saturated brine in order anddried over anhydrous sodium sulfate. The solvent was then evaporatedunder reduced pressure. The residues were purified by silica gel columnchromatography (5% ethyl acetate/hexane) to obtain the title compound(0.36 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 8.16 (1H, d, J=8.2 Hz), 7.96 (1H, d, J=1.6 Hz), 7.78(1H, dd, J=8.2, 1.6 Hz), 3.94 (3H, s), 3.30-3.25 (2H, m), 3.04-3.00 (2H,m).

Reference Example 6 5,6,7,8-Tetrahydroquinolin-5-one N-oxide

5,6,7,8-Tetrahydroquinolin-5-one (7.12 g) was dissolved indichloromethane (138 mL), added with 3-chloroperbenzoic acid (14.5 g)under ice cooling, and stirred for 4 hours at the same temperature.After adding a saturated aqueous solution of sodium hydrogen carbonateand diluting with chloroform, insoluble was removed by filtrationthrough Celite. After adding 1 mol/L aqueous solution of sodiumhydroxide, it was extracted with chloroform and dried over anhydroussodium sulfate. The solvent was then evaporated under reduced pressure.The residues were suspended in diethyl ether and collected by filtrationto obtain the title compound (6.61 g) as a yellow powder.

¹H-NMR (CDCl₃) δ: 8.44 (1H, dd, J=6.4, 0.9 Hz), 7.87 (1H, dd, J=8.0, 0.9Hz), 7.32-7.25 (1H, m), 3.24 (2H, t, J=6.2 Hz), 2.74-2.65 (2H, m),2.28-2.17 (2H, m)

Reference Example 7 2-Cyano-5,6,7,8-tetrahydroquinolin-5-one

Reference Example 6 (6.59 g) was dissolved in dichloromethane (81 mL),added with trimethylsilyl cyanide (17.9 mL) and N, N-dimethylcarbamoylchloride (8.19 mL) under ice cooling, and stirred for 2.3 hours at roomtemperature and for 4.5 hours at 30° C. After cooling to roomtemperature, 2 mol/L aqueous solution of sodium hydroxide was added andstirred vigorously. After that, extraction with chloroform wasperformed. It was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residues were purified bysilica gel column chromatography (4 to 30% ethyl acetate/hexane) toobtain the title compound (6.07 g) as a pale yellow powder.

¹H-NMR (CDCl₃) δ: 8.40 (1H, d, J=8.0 Hz), 7.68 (1H, d, J=8.0 Hz), 3.21(2H, t, J=6.3 Hz), 2.79-2.72 (2H, m), 2.31-2.18 (2H, m)

Reference Example 8 5-Oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

Reference Example 7 (6.05 g) was added with conc. hydrochloric acid (70mL) and stirred for 14 hours under reflux with heating. After cooling toroom temperature, conc. hydrochloric acid was evaporated under reducedpressure. The residues were dissolved in a solution of 25%methanol/chloroform, washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residues were suspended in diisopropyl ether andcollected by filtration to obtain the title compound (6.38 g) as a paleyellow powder.

¹H-NMR (CDCl₃) δ: 8.53 (1H, d, J=8.0 Hz), 8.19 (1H, d, J=8.0 Hz), 3.23(2H, t, J=6.3 Hz), 2.81-2.75 (2H, m), 2.32-2.21 (2H, m)

Reference Example 9 Methyl5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylate

According to the same method as Reference Example 3, the title compound(731 mg) was obtained as a pale yellow powder from Reference Example 8(980 mg).

¹H-NMR (CDCl₃) δ: 8.42 (1H, d, J=8.1 Hz), 8.09 (1H, d, J=8.1 Hz), 4.03(3H, s), 3.27 (2H, t, J=6.0 Hz), 2.78-2.72 (2H, m), 2.30-2.18 (2H, m)

Reference Example 10 2,3-Dihydro-3-oxobenzofuran-6-yltrifluoromethanesulfonate

2,3-Dihydro-6-hydroxy-3-oxobenzofuran (2.00 g) was dissolved indichloromethane (22 mL), added with pyridine (5.39 mL), and addeddropwise with trifluoromethanesulfonic anhydride (2.69 mL) under icecooling. After stirring at the same temperature for 2 hours, the solventwas evaporated under reduced pressure. The residues were diluted withethyl acetate, washed with water and saturated brine in order, and driedover anhydrous sodium sulfate. After the solvent was evaporated underreduced pressure, the residues were purified by silica gel columnchromatography (5 to 20% ethyl acetate/hexane), suspended in a mixturesolution of hexane/diisopropyl ether, and collected by filtration toobtain the title compound (1.84 g) as a yellow powder.

¹H-NMR (CDCl₃) δ: 7.77 (1H, d, J=8.4 Hz), 7.10 (1H, d, J=2.0 Hz), 7.02(1H, dd, J=8.4, 2.0 Hz), 4.73 (2H, s)

Reference Example 11 2,3-Dihydro-3-hydroxybenzofuran-6-yltrifluoromethanesulfonate

Reference Example 10 (940 mg) was dissolved in THF (15 mL), added withsodium borohydride (146 mg) in several divided portions under icecooling, and stirred at the same temperature for 1.5 hours. Under icecooling, a saturated aqueous solution of ammonium chloride was addedfollowed by extraction with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residues werepurified by silica gel column chromatography (6 to 35% ethylacetate/hexane) to obtain the title compound (785 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 7.47 (1H, d, J=8.2 Hz), 6.86 (1H, dd, J=8.2, 2.2 Hz),6.80 (1H, d, J=2.2 Hz), 5.40 (1H, ddd, J=6.8, 6.8, 2.8 Hz), 4.66 (1H,dd, J=10.9, 6.8 Hz), 4.53 (1H, dd, J=10.9, 2.8 Hz), 2.01 (1H, d, J=6.8Hz).

Reference Example 12 Methyl2,3-dihydro-3-hydroxybenzofuran-6-carboxylate

Reference Example 11 (155 mg) was dissolved in DMF (3.0 mL), added withmethanol (0.40 mL), triethylamine (0.38 mL),1,3-bis(diphenylphosphino)propane (11.2 mg), and palladium acetate (II)(6.10 mg), and stirred in a carbon monoxide atmosphere under ordinarypressure at for 3 hours. After cooling to room temperature, it wasdiluted with water and extracted with diethyl ether. The organic layerwas washed with water and saturated brine in order and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residues were purified by silica gel column chromatography(33% ethyl acetate/hexane) to obtain the title compound (75.0 mg) as alight pink powder.

¹H-NMR (CDCl₃) δ: 7.66 (1H, dd, J=7.7, 1.5 Hz), 7.52 (1H, d, J=1.5 Hz),7.47 (1H, d, J=7.7 Hz), 5.41 (1H, ddd, J=6.8, 6.8, 2.9 Hz), 4.62 (1H,dd, J=10.8, 6.8 Hz), 4.50 (1H, dd, J=10.8, 2.9 Hz), 3.91 (3H, s), 2.05(1H, d, J=6.8 Hz)

Reference Example 13 4-Oxoisochromane-7-yl trifluoromethanesulfonate

According to the same method as Reference Example 10, the title compound(1.70 g) was obtained as a white powder from 7-hydroxyisochroman-4-one(1.00 g).

¹H-NMR (CDCl₃) δ: 8.16 (1H, d, J=8.6 Hz), 7.32 (1H, dd, J=8.6, 2.4 Hz),7.18 (1H, d, J=2.4 Hz), 4.93 (2H, s), 4.40 (2H, s).

Reference Example 14 Methyl 4-oxoisochromane-7-carboxylate

According to the same method as Reference Example 12, the title compound(588 mg) was obtained as a white powder from Reference Example 13 (1.50g).

¹H-NMR (CDCl₃) δ: 8.13-8.04 (2H, m), 7.92 (1H, s), 4.94 (2H, s), 4.41(2H, s), 3.96 (3H, s).

Reference Example 15 Methyl5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylate

According to the same method as Reference Example 11, the title compound(526 mg) was obtained as a white powder from methyl5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylate (523 mg).

¹H-NMR (CDCl₃) δ: 7.88 (1H, dd, J=8.1, 1.6 Hz), 7.77 (1H, d, J=1.6 Hz),7.56 (1H, d, J=8.1 Hz), 5.01-4.96 (1H, m), 3.90 (3H, s), 2.99-2.91 (1H,m), 2.79-2.71 (1H, m), 2.08-1.97 (2H, m), 1.89 (1H, d, J=4.0 Hz),1.85-1.68 (3H, m), 1.46-1.33 (1H, m).

Compounds of Reference Examples 16 to 18 which have been producedaccording to the same method as Reference Example 15 by using thecompound of Reference Examples 5, 9 and 14 are shown in Table 1.

TABLE 1 Refer- ence Exam- Structural ple formula ¹H-NMR 16

(CDCl₃) δ: 7.82 (1H, d, J = 1.8 Hz), 7.70 (1H, dd, J = 8.1, 1.8 Hz),7.42 (1H, d, J = 8.1 Hz), 4.83 (1H, ddd, J = 8.8, 5.0, 3.3 Hz), 3.90(3H, s), 3.30 (1H, ddd, J = 12.7, 11.0, 3.3 Hz), 2.93 (1H, ddd, J =12.7, 6.1, 3.7 Hz), 2.34 (1H, dddd, J = 13.9, 8.8, 6.1, 3.3 Hz), 2.10(1H, dddd, J = 13.9, 11.0, 3.7, 3.3 Hz), 1.94 (1H, d, J = 5.0 Hz). 17

(CDCl₃) δ: 7.99 (1H, d, J = 8.1 Hz), 7.95 (1H, d, J = 8.1 Hz), 4.91-4.82(1H, m), 3.99 (3H, s), 3.18-2.93 (2H, m), 2.23- 2.00 (2H, m), 1.96 (1H,d, J = 6.4 Hz), 1.93-1.77 (2H, m). 18

(CDCl₃) δ: 7.93 (1H, d, J = 8.0 Hz), 7.70 (1H, s), 7.53 (1H, d, J = 8.0Hz), 4.82 (1H, d, J = 15.3 Hz), 4.70 (1H, d, J = 15.3 Hz), 4.63-4.56(1H, m), 4.09 (1H, dd, J = 12.0, 3.2 Hz), 3.94-3.87 (1H, m), 3.92 (3H,s), 2.46 (1H, d, J = 9.3 Hz).

Reference Example 19 4-(Phenylsulfanylmethyl)benzyl alcohol

Methyl 4-(phenylsulfanylmethyl)benzoate (1.07 g) was dissolved in THF(14 mL), added with lithium aluminum hydride (200 mg) in small portionsunder ice cooling, and stirred for 40 minutes at the same temperature.Under ice cooling, sodium sulfate decahydrate was added in smallportions and filtered through Celite. The solvent was evaporated underreduced pressure. The residues were suspended in hexane and collected byfiltration to obtain the title compound (910 mg) as a white powder.

¹H-NMR (DMSO-D₆) 7.34-7.12 (9H, m), 5.10 (1H, t, J=5.7 Hz), 4.44 (2H, d,J=5.7 Hz), 4.21 (2H, s)

Reference Example 20N-[4-(Tetrahydro-2H-pyran-2-yloxymethyl)benzyl]-N-phenyl-2-nitrobenzenesulfonamide

N-Phenyl-2-nitrobenzenesulfone amide (1.95 g) was dissolved in DMF (15mL), added with a DMF (3 mL) solution of potassium carbonate (1.16 g)and 2-(4-chloromethylbenzyloxyl)tetrahydro-2H-pyrane (2.02 g) under icecooling and stirred for 18 hours at 40° C. After cooling to roomtemperature, the solvent was evaporated under reduced pressure. Theresidues were suspended in water and extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine in order anddried over anhydrous sodium sulfate. The solvent was then evaporatedunder reduced pressure. The residues were purified by silica gel columnchromatography (33% ethyl acetate/hexane) to obtain the title compound(3.29 g) as a yellow oil.

¹H-NMR (CDCl₃) δ: 7.66-7.64 (2H, m), 7.54-7.42 (2H, m), 7.27-7.17 (7H,m), 7.12-7.06 (2H, m), 4.95 (2H, s), 4.73 (1H, d, J=12.1 Hz), 4.68-4.66(1H, m), 4.45 (1H, d, J=12.1 Hz), 3.92-3.85 (1H, m), 3.54-3.49 (1H, m),1.89-1.51 (6H, m).

Reference Example 21N-(4-Hydroxymethylbenzyl)-N-phenyl-2-nitrobenzenesulfonamide

Reference Example 20 (3.37 g) was dissolved in methanol (35 mL), addedwith p-toluenesulfonic acid monohydrate (133 mg), and stirred for 30minutes at room temperature. The solvent was evaporated under reducedpressure and the residues were dissolved in ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in order and dried over anhydrous sodiumsulfate. The solvent was then evaporated under reduced pressure. Theresidues were purified by silica gel column chromatography (50% ethylacetate/hexane) to obtain the title compound (2.57 g) as a pale yellowpowder.

¹H-NMR (CDCl₃) δ: 7.66-7.65 (2H, m), 7.54-7.43 (2H, m), 7.26-7.17 (7H,m), 7.10-7.06 (2H, m), 4.95 (2H, s), 4.64 (2H, d, J=5.1 Hz), 1.63 (1H,t, J=5.1 Hz).

Reference Example 22 4-(3-Methyl-1-butyn-1-yl)benzyl alcohol

4-Iodobenzyl alcohol (1.00 g) was dissolved in DMF (17 mL), added withcopper (1) iodide (97.7 mg), triethylamine (0.89 mL), and3-methyl-1-butyne (1.27 mL), and stirred for 10 minutes in argonatmosphere. Subsequently, it was added withbis(triphenylphosphine)palladium (II) chloride (300 mg) and stirred for4.3 hours at room temperature in argon atmosphere. After filtrationthrough Celite, it was washed with ethyl acetate and the solvent wasevaporated under reduced pressure. The residues were purified by silicagel column chromatography (6 to 40% ethyl acetate/hexane) to obtain thetitle compound as a yellow oil.

¹H-NMR (CDCl₃) δ: 7.38 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz), 4.67(2H, d, J=5.5 Hz), 2.85-2.70 (1H, m), 1.66 (1H, t, J=5.5 Hz), 1.26 (6H,d, J=7.0 Hz).

Compounds of Reference Examples 23 to 24, which have been produced byusing the corresponding materials according to the same method asReference Example 22, are shown in Table 2.

TABLE 2 Reference Structural Example formula ¹H-NMR 23

(CDCl₃) δ: 7.36 (2H, d, J = 8.3 Hz), 7.26 (2H, d, J = 8.3 Hz), 4.67 (2H,d, J = 4.9 Hz), 1.66 (1H, br s), 1.50-1.39 (1H, m), 0.91-0.76 (4H, m).24

(CDCl₃) δ: 7.39 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz), 4.67 (2H,s), 2.64-2.53 (1H, m), 1.94-1.82 (2H, m), 1.82-1.69 (2H, m), 1.68-1.45(3H, m), 1.44-1.29 (3H, m).

Reference Example 25 4-((E)-2-Cyclohexylvinyl)benzyl alcohol

4-Iodobenzyl alcohol (2.34 g) was dissolved in DMF (40 mL), added withvinylcyclohexane (1.32 g), triethylamine (1.81 mL), andbis(triphenylphosphine)palladium (II) chloride (700 mg), and stirred for23 hours at 80° C. After cooling to room temperature, the solvent wasevaporated under reduced pressure, and the residues were purified bysilica gel column chromatography (8 to 30% ethyl acetate/hexane) toobtain the title compound (672 mg) as a yellow solid.

¹H-NMR (CDCl₃) δ: 7.34-7.19 (4H, m), 6.29 (1H, d, J=16.0 Hz), 6.13 (1H,dd, J=16.0, 6.8 Hz), 4.67-4.56 (3H, m), 2.15-2.00 (1H, m), 1.82-1.51(4H, m), 1.37-1.04 (6H, m)

Reference Example 26 4-(2-Cyclohexylethyl)benzyl alcohol

Reference Example 25 (283 mg) was dissolved in methanol (7.0 mL), addedwith palladium-fibroin (57.0 mg), and stirred in a hydrogen atmosphereunder ordinary pressure at room temperature for 45 minutes. Afterfiltration through Celite, it was washed with methanol and the solventwas evaporated under reduced pressure. The residues were purified bysilica gel column chromatography (5 to 35% ethyl acetate/hexane) toobtain the title compound (206 mg) as a yellow powder.

¹H-NMR (CDCl₃) δ: 7.27 (2H, d, J=8.1 Hz), 7.17 (2H, d, J=8.1 Hz), 4.66(2H, d, J=5.9 Hz), 2.66-2.57 (2H, m), 1.82-1.60 (5H, m), 1.57-1.44 (3H,m), 1.32-1.10 (4H, m), 1.01-0.85 (2H, m)

Reference Example 27 Methyl trans-4-((E)-2-phenylvinyl)cyclohexanecarboxylate

According to the same method as Reference Example 25, the title compound(326 mg) was obtained as a brown solid from methyltrans-4-vinylcyclohexane carboxylate (492 mg).

¹H-NMR (CDCl₃) δ: 7.39-7.12 (5H, m), 6.36 (1H, d, J=15.9 Hz), 6.14 (1H,dd, J=15.9, 7.0 Hz), 3.68 (3H, s), 2.35-2.21 (1H, m), 2.19-1.99 (3H, m),1.97-1.87 (2H, m), 1.60-1.43 (2H, m), 1.30-1.14 (2H, m)

Reference Example 28 trans-4-((E)-2-Phenylvinyl)cyclohexylmethyl alcohol

According to the same method as Reference Example 19, the title compound(99.0 mg) was obtained as a white powder from Reference Example 27 (120mg).

¹H-NMR (CDCl₃) δ: 7.38-7.22 (4H, m), 7.21-7.14 (1H, m), 6.36 (1H, d,J=16.0 Hz), 6.16 (1H, dd, J=16.0, 7.0 Hz), 3.48 (2H, d, J=6.2 Hz),2.17-2.01 (1H, m), 1.95-1.79 (4H, m), 1.64-1.31 (2H, m), 1.30-1.15 (2H,m), 1.12-0.96 (2H, m)

Reference Example 29 Methyl trans-4-(2-phenylethyl)cyclohexanecarboxylate

Reference Example 27 (200 mg) was dissolved in methanol (5.0 mL), addedwith 5% palladium-carbon (80.0 mg), and stirred in a hydrogen atmosphereunder 3 atm at room temperature for 7.3 hours. After filtration throughCelite, it was washed with methanol and the solvent was evaporated underreduced pressure. The residues were diluted with ethyl acetate, washedwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residues werepurified by silica gel column chromatography (5% ethyl acetate/hexane)to obtain the title compound (192 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 7.31-7.23 (2H, m), 7.21-7.11 (3H, m), 3.66 (3H, s),2.66-2.58 (2H, m), 2.25 (1H, tt, J=12.3, 3.5 Hz), 2.03-1.93 (2H, m),1.92-1.83 (2H, m), 1.57-1.20 (5H, m), 0.97 (2H, ddd, J=16.3, 13.4, 3.5Hz)

Reference Example 30 trans-4-(2-Phenylethyl)cyclohexylmethyl alcohol

According to the same method as Reference Example 19, the title compound(166 mg) was obtained as a colorless oil from Reference Example 29 (190mg).

¹H-NMR (CDCl₃) δ: 7.31-7.23 (2H, m), 7.21-7.12 (3H, m), 3.45 (2H, d,J=6.4 Hz), 2.66-2.59 (2H, m), 1.91-1.74 (4H, m), 1.60-1.16 (5H, m),1.06-0.82 (4H, m).

Reference Example 31 Methyl cis-4-((E)-2-phenylvinyl)cyclohexanecarboxylate

Benzyltriphenylphosphonium bromide (2.94 g) was dissolved in THF (23.0mL), added at −20° C. with potassium tert-butoxide (1.07 g) in smallportions, and stirred for 1 hour at the same temperature. Subsequently,a THF (6.0 mL) solution of methyl cis-4-formylcyclohexane carboxylate(1.00 g) was added dropwise over 35 minutes, and stirred for 1.6 hoursat the same temperature. After raising the temperature to roomtemperature, it was stirred after adding water and extracted withtoluene. The organic layer was washed with water and saturated brine inorder. After drying over anhydrous sodium sulfate, the solvent wasevaporated under reduced pressure. The residues were purified by silicagel column chromatography (9% ethyl acetate/hexane) to obtain the titlecompound (268 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 7.37-7.15 (5H, m), 6.37 (1H, d, J=16.6 Hz), 6.22 (1H,dd, J=16.6, 6.6 Hz), 3.69 (3H, s), 2.62-2.50 (1H, m), 2.38-2.24 (1H, m),2.10-2.00 (3H, m), 1.76-1.42 (5H, m)

Reference Example 32 Methyl cis-4-(2-phenylethyl)cyclohexane carboxylate

According to the same method as Reference Example 29, the title compound(248 mg) was obtained as a colorless oil from Reference Example 31 (268mg).

¹H-NMR (CDCl₃) δ: 7.31-7.23 (2H, m), 7.20-7.13 (3H, m), 3.68 (3H, s),2.64-2.48 (3H, m), 2.05-1.92 (2H, m), 1.67-1.23 (9H, m)

Reference Example 33 cis-4-(2-Phenylethyl)cyclohexylmethyl alcohol

According to the same method as Reference Example 19, the title compound(208 mg) was obtained as a colorless oil from Reference Example 32 (248mg).

¹H-NMR (CDCl₃) δ: 7.31-7.24 (2H, m), 7.21-7.14 (3H, m), 3.54 (2H, t,J=5.3 Hz), 2.64-2.56 (2H, m), 1.72-1.32 (12H, m), 1.25-1.18 (1H, m)

Reference Example 34 6-Thiochromanecarbaldehyde

6-Bromo-thiochromane (1.00 g) was dissolved in THF (15.0 mL), addeddropwise with 2.69 mol/L n-butyl lithium/hexane solution (3.24 mL) at−78° C., and stirred for 1 hour at the same temperature. After addingDMF (0.71 mL) at the same temperature, it was stirred for 16 hours whileraising the temperature to room temperature. A saturated aqueoussolution of ammonium chloride was added, and after extraction with ethylacetate, the organic layer was washed with saturated brine. After dryingover anhydrous sodium sulfate, the solvent was evaporated under reducedpressure and the residues were purified by silica gel columnchromatography (2 to 15% ethyl acetate/hexane) to obtain the titlecompound (342 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 9.85 (1H, s), 7.57-7.48 (2H, m), 7.21 (1H, d, J=8.1Hz), 3.12-3.05 (2H, m), 2.89 (2H, t, J=6.1 Hz), 2.20-2.10 (2H, m)

Reference Example 35 6-Thiochromanemethyl alcohol

Reference Example 34 (340 mg) was dissolved in methanol (10 mL), addedwith sodium borohydride (91.2 mg) in several divided portions under icecooling, and stirred at the same temperature for 1 hour. Under icecooling, a saturated aqueous solution of ammonium chloride was addedfollowed by stirring. The solvent was evaporated under reduced pressure.After dilution with ethyl acetate, it was washed with water andsaturated brine in order. After drying over anhydrous sodium sulfate,the solvent was evaporated under reduced pressure, and the residues werepurified by silica gel column chromatography (6 to 50% ethylacetate/hexane) to obtain the title compound as a colorless oil.

¹H-NMR (CDCl₃) δ: 7.11-7.01 (3H, m), 4.58 (2H, d, J=5.1 Hz), 3.06-2.98(2H, m), 2.81 (2H, t, J=6.1 Hz), 2.17-2.05 (2H, m)

Reference Example 36 1-Oxo-6-phenylethynyl-1,2,3,4-tetrahydronaphthalene

According to the same method as Reference Example 22, the title compound(1.10 g) was obtained as a yellow powder from5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.47g).

¹H-NMR (CDCl₃) δ: 8.01 (1H, d, J=7.9 Hz), 7.56-7.51 (2H, m), 7.46-7.34(5H, m), 2.96 (2H, t, J=6.0 Hz), 2.67 (2H, t, J=6.6 Hz), 2.15 (2H, tt,J=6.6, 6.0 Hz).

Reference Example 371-Hydroxy-6-phenylethynyl-1,2,3,4-tetrahydronaphthalene

According to the same method as Reference Example 11, the title compound(485 mg) was obtained as a white powder from Reference Example 36 (493mg).

¹H-NMR (CDCl₃) δ: 7.58-7.48 (2H, m), 7.43-7.29 (6H, m), 4.79-4.75 (1H,m), 2.87-2.66 (2H, m), 2.08-1.73 (4H, m), 1.59 (1H, bRS).

Reference Example 381-Hydroxy-6-(2-phenylethyl)-1,2,3,4-tetrahydronaphthalene

According to the same method as Reference Example 26, the title compound(423 mg) was obtained as a colorless oil from Reference Example 37 (482mg).

¹H-NMR (CDCl₃) δ: 7.37-7.17 (6H, m), 7.05 (1H, dd, J=7.7, 1.6 Hz), 6.95(1H, d, J=1.6 Hz), 4.80-4.75 (1H, m), 2.95-2.64 (6H, m), 2.01-1.72 (4H,m), 1.63 (1H, d, J=6.2 Hz).

Reference Example 39 4-(Phenylsulfanylmethyl)benzyl chloride

Reference Example 19 (77.0 mg) was dissolved in dichloromethane (2.0mL), added with thionyl chloride (30 μL), and stirred for 1.8 hours. Thesolvent and reagents were evaporated under reduced pressure to obtainthe crude product of the title compound as white amorphous.

¹H-NMR (CDCl₃) δ: 7.34-7.14 (9H, m), 4.56 (2H, s), 4.10 (2H, s)

Compounds of Reference Examples 40 to 46, which have been produced byusing the corresponding materials according to the same method asReference Example 39, are shown in Table 3.

TABLE 3 Reference Structural Example formula ¹H-NMR 40

(CDCl₃) δ: 7.67-7.64 (2H, m), 7.54-7.43 (2H, m), 7.30-7.18 (7H, m),7.11-7.07 (2H, m), 4.96 (2H, s), 4.53 (2H, s). 41

(CDCl₃) δ: 7.37 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 4.56 (2H,s), 2.85-2.70 (1H, m), 1.26 (6H, d, J = 7.0 Hz). 42

(CDCl₃) δ: 7.35 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 4.55 (2H,s), 1.50-1.39 (1H, m), 0.92-0.76 (4H, m). 43

(CDCl₃) δ: 7.38 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 4.56 (2H,s), 2.58 (1H, tt, J = 9.1, 3.8 Hz), 1.93-1.82 (2H, m), 1.82-1.69 (2H,m), 1.61- 1.46 (3H, m), 1.43-1.28 (3H, m). 44

(CDCl₃) δ: 7.40-7.27 (4H, m), 6.33 (1H, d, J = 16.0 Hz), 6.19 (1H, dd, J= 16.0, 6.6 Hz), 4.57 (2H, s), 2.23-2.04 (1H, m), 1.93-1.62 (6H, m),1.43- 1.07 (4H, m). 45

(CDCl₃) δ: 7.29 (2H, d, J = 8.3 Hz), 7.16 (2H, d, J = 8.3 Hz), 4.57 (2H,s), 2.65-2.57 (2H, m), 1.81-1.58 (5H, m), 1.57- 1.44 (2H, m), 1.35-1.06(4H, m), 1.02-0.83 (2H, m). 46

(CDCl₃) δ: 7.08-7.06 (2H, m), 7.04 (1H, d, J = 1.3 Hz), 4.51 (2H, s),3.07-2.99 (2H, m), 2.81 (2H, t, J = 6.1 Hz), 2.17- 2.06 (2H, m).

Reference Example 472-{2-[(E)-2-[4-((E)-2-Phenylvinyl)phenyl]vinyl]phenyl}ethanol

According to the same method as Reference Example 25, the title compound(4.80 g) was obtained as a yellow solid from 2-(2-bromophenyl)ethylalcohol (3.42 g) and 4-vinyl-trans-stilbene (4.21 g).

¹H-NMR (DMSO-D₆) δ: 7.69-7.60 (7H, m), 7.50 (1H, d, J=16.2 Hz),7.41-7.35 (2H, m), 7.29-7.20 (6H, m), 7.12 (1H, d, J=16.2 Hz), 4.73 (1H,t, J=5.7 Hz), 3.57 (2H, td, J=7.0, 5.7 Hz), 2.93 (2H, t, J=7.0 Hz).

Reference Example 482-{2-[2-[4-(2-Phenylethyl)phenyl]ethyl]phenyl}ethanol

According to the same method as Reference Example 29, the title compound(4.56 g) was obtained as a colorless oil from Reference Example 47 (4.80g).

¹H-NMR (DMSO-D₆) δ: 7.36-7.22 (4H, m), 7.20-7.08 (9H, m), 4.69 (1H, t,J=5.5 Hz), 3.55 (2H, td, J=7.1, 5.5 Hz), 2.86-2.80 (4H, m), 2.84 (2H, t,J=7.1 Hz), 2.79-2.74 (2H, m), 2.75 (2H, t, J=6.3 Hz).

Reference Example 492-{2-[2-[4-(2-Phenylethyl)phenyl]ethyl]phenyl}acetaldehyde

Reference Example 48 (496 mg) was dissolved in DMSO (10 mL), added withIBX (840 mg), and stirred for 1.5 hours at room temperature. It wasadded with ethyl acetate and water in order and stirred for 1 hour atroom temperature. The precipitates were filtered and washed with ethylacetate. After liquid fractionation, the organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. After that, thesolvent was evaporated under reduced pressure. The residues werepurified by silica gel column chromatography (10 to 30% ethylacetate/hexane) to obtain the title compound (422 mg) as a colorlessoil.

¹H-NMR (DMSO-D6) δ: 9.62 (1H, t, J=1.7 Hz), 7.27-7.22 (5H, m), 7.20-7.15(4H, m), 7.13-7.07 (4H, m), 3.77 (2H, d, J=1.7 Hz), 2.83 (4H, s),2.74-2.72 (4H, m).

Reference Example 50 Methyl5-[2-(2-{2-[4-(2-phenylethyl)phenyl]ethyl}phenyl)ethylamino]-5,6,7,8-tetrahydronaphthalene-2-carboxylate

In a argon atmosphere, methyl5-amino-5,6,7,8-tetrahydronaphthalene-2-carboxylate hydrochloride (311mg) was dissolved in dichloromethane (26 mL), added with triethylamine(0.18 mL), and stirred for 5 minutes at room temperature. ReferenceExample 49 (422 mg) and acetic acid (0.11 mL) were added in order andstirred for 10 minutes at the same temperature. Subsequently, sodiumtriacetoxyborohydride (681 mg) was added under ice cooling followed bystirring for 2 hours at room temperature. A saturated aqueous solutionof sodium hydrogen carbonate was added, and extracted with ethyl acetateand dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure. The residues were purified by silica gel columnchromatography (30 to 70% ethyl acetate/hexane) to obtain the titlecompound (607 mg) as a colorless oil.

¹H-NMR (DMSO-D₆) δ: 7.68-7.63 (2H, m), 7.50 (1H, d, J=8.4 Hz), 7.29-7.08(13H, m), 3.80 (3H, s), 3.73 (1H, bRS), 2.85-2.79 (7H, m), 2.76-2.75(8H, m), 1.93-1.56 (4H, m).

Reference Example 51N-[2-(2-Methoxymethoxyphenyl)ethyl]-2-nitrobenzenesulfonamide

Reference Example 2 (6.72 g) was dissolved in dichloromethane (186 mL),added under ice cooling with triethylamine (5.67 mL) and2-nitrobenzenesulfonyl chloride (10.1 g), and stirred for 1 hour at thesame temperature. The solvent was evaporated under reduced pressure. Theresidues were suspended in ethyl acetate, washed with water andsaturated brine in order, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure and the residues werepurified by silica gel column chromatography (20% ethyl acetate/hexane)to obtain the title compound (11.0 g) as a yellow oil.

¹H-NMR (CDCl₃) δ: 8.10-8.05 (1H, m), 7.83-7.79 (1H, m), 7.72-7.66 (2H,m), 7.18-7.12 (1H, m), 7.04-7.01 (2H, m), 6.86 (1H, ddd, J=8.6, 7.5, 1.3Hz), 5.51 (1H, t, J=5.5 Hz), 5.19 (2H, s), 3.46 (3H, s), 3.39 (2H, td,J=6.9, 5.5 Hz), 2.87 (2H, t, J=6.9 Hz).

Reference Example 52N-{2-[2-[4-(2-Phenylethyl)benzyloxy]phenyl]ethyl}-2-nitrobenzenesulfonamide

According to the same method as Reference Example 51, the title compound(2.47 g) was obtained as a yellow oil from2-{2-[4-(2-phenylethyl)benzyloxy]phenyl}ethylamine (1.83 g).

¹H-NMR (CDCl₃) δ: 7.97 (1H, dd, J=7.6, 1.7 Hz), 7.76 (1H, dd, J 7.3, 1.8Hz), 7.66-7.55 (2H, m), 7.37-7.12 (10H, m), 7.01 (1H, dd, J=7.3, 1.6Hz), 6.86-6.78 (2H, m), 5.43 (1H, t, J=5.7 Hz), 5.00 (2H, s), 3.40 (2H,td, J=6.8, 5.7 Hz), 2.94 (4H, s), 2.86 (2H, t, J=6.8 Hz).

Reference Example 53 Methyl1-{N-[2-(2-methoxymethoxyphenyl)ethyl]-(2-nitrobenzenesulfonamide)}indane-5-carboxylate

Reference Example 51 (733 mg) was dissolved in toluene (10 mL), addedunder ice cooling with methyl 1-hydroxyindane-5-carboxylate (577 mg),tri-n-butylphosphine (0.75 mL) and 1,1′-azobis(N,N-dimethylformamide)(517 mg), and stirred for 14.5 hours at room temperature. The solventwas evaporated under reduced pressure. The residues were dissolved againin ethyl acetate. It was washed with water and saturated brine in order,and dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure and the residues were purified by silica gelcolumn chromatography (20% ethyl acetate/hexane) to obtain the titlecompound as a yellow oil.

¹H-NMR (CDCl₃) δ: 8.19-8.16 (1H, m), 7.92 (1H, s), 7.86-7.83 (1H, m),7.74-7.66 (3H, m), 7.29-7.25 (1H, m), 7.14-7.08 (1H, m), 6.97-6.93 (2H,m), 6.85 (1H, ddd, J=8.4, 7.4, 1.1 Hz), 5.66-5.61 (1H, m), 5.00 (1H, d,J=6.8 Hz), 4.95 (1H, d, J=6.8 Hz), 3.90 (3H, s), 3.38-3.19 (2H, m), 3.27(3H, s), 3.13-2.78 (3H, m), 2.67-2.49 (2H, m), 2.23-2.11 (1H, m).

Compounds of Reference Examples 54 to 61, which have been produced byusing the corresponding compound (4) and the compound of ReferenceExample 51 or 52 according to the same method as Reference Example 53,are shown in Table 4 and Table 5.

TABLE 4 Reference Structural Example formula ¹H-NMR 54

(CDCl₃) δ: 8.18-8.15 (1H, m), 7.77- 7.64 (5H, m), 7.35 (1H, d, J = 8.2Hz), 7.15-7.09 (1H, m), 7.03 (1H, dd, J = 7.3, 1.6 Hz), 6.96 (1H, d, J =7.5 Hz), 6.87 (1H, ddd, J = 8.3, 7.3, 0.9 Hz), 5.29 (1H, dd, J = 9.9,6.0 Hz), 5.04 (1H, d, J = 6.8 Hz), 5.00 (1H, d, J = 6.8 Hz), 3.89 (3H,s), 3.53-3.42 (1H, m), 3.32-3.19 (1H, m), 3.28 (3H, s), 2.92-2.73 (4H,m), 2.27-2.17 (1H, m), 2.09-1.84 (3H, m). 55

(CDCl₃) δ: 8.02 (1H, dd, J = 8.0, 1.2 Hz), 7.69-7.52 (5H, m), 7.32-7.10(11H, m), 7.04 (1H, dd, J = 7.4, 1.7 Hz), 6.86-6.80 (2H, m), 5.24-5.19(1H, m), 4.94 (1H, d, J = 11.5 Hz), 4.87 (1H, d, J = 11.5 Hz), 3.86 (3H,s), 3.57-3.46 (1H, m), 3.22-3.12 (1H, m), 2.94 (4H, s), 2.88-2.62 (3H,m), 2.51-2.40 (1H, m), 2.10-1.99 (1H, m), 1.93-1.71 (3H, m). 56

(CDCl₃) δ: 7.97 (1H, dd, J = 7.5, 1.3 Hz), 7.73 (1H, d, J = 1.8 Hz),7.61- 7.47 (4H, m), 7.21-7.13 (2H, m), 7.07-7.03 (2H, m), 6.94 (1H, ddd,J = 8.4, 7.3, 1.1 Hz), 5.46-5.43 (1H, m), 5.17 (2H, s), 4.09-3.98 (1H,m), 3.86 (3H, s), 3.53-3.42 (1H, m), 3.40 (3H, s), 3.06-3.00 (2H, m),2.95-2.91 (2H, m), 2.44-2.40 (1H, m), 2.03-1.78 (4H, m), 1.40-1.30 (1H,m). 57

(CDCl₃) δ: 8.04 (1H, d, J = 8.4 Hz), 7.72-7.64 (2H, m), 7.59-7.52 (1H,m), 7.47-7.42 (2H, m), 7.32-7.10 (11H, m), 6.99 (1H, dd, J = 7.6, 1.5Hz), 6.87-6.80 (2H, m), 5.36 (1H, dd, J = 10.7, 6.1 Hz), 4.94 (1H, d, J= 11.4 Hz), 4.90 (1H, d, J = 11.4 Hz), 4.15- 4.07 (2H, m), 3.85 (3H, s),3.61-3.46 (1H, m), 3.15-3.02 (1H, m), 2.94 (4H, s), 2.85-2.67 (2H, m),2.30-2.08 (2H, m). 58

(CDCl₃) δ: 8.01 (1H, dd, J = 8.1, 0.9 Hz), 7.75-7.49 (6H, m), 7.31-7.11(10H, m), 7.00 (1H, dd, J = 7.7, 1.7 Hz), 6.87-6.80 (2H, m), 5.22 (1H,dd, J = 11.2, 4.3 Hz), 4.97 (1H, d, J = 11.5 Hz), 4.92 (1H, d, J = 11.5Hz), 3.85 (3H, s), 3.67-3.55 (1H, m), 3.40-3.16 (3H, m), 2.96-2.67 (6H,m), 2.46-2.10 (2H, m).

TABLE 5 59

(CDCl₃) δ: 8.02 (1H, dd, J = 8.1, 1.3 Hz), 7.85 (1H, d, J = 8.1 Hz),7.80 (1H, dd, J = 8.1, 0.5 Hz), 7.72-7.63 (2H, m), 7.56 (1H, ddd, J =8.1, 6.6, 2.2 Hz), 7.32-7.16 (9H, m), 7.13 (1H, dd, J = 8.1, 1.3 Hz),7.01 (1H, dd, J = 8.1, 1.3 Hz), 6.88-6.80 (2H, m), 5.30-5.21 (1H, m),4.93 (1H, d, J = 11.2 Hz), 4.87 (1H, d, J = 11.2 Hz), 3.95 (3H, s), 3.51(1H, ddd, J = 14.6, 11.5, 5.2 Hz), 3.15 (1H, ddd, J = 14.6, 11.5, 5.2Hz), 3.04- 2.87 (1H, m), 2.94 (4H, s), 2.79-2.59 (3H, m), 2.13- 2.00(1H, m), 1.92-174 (3H, m). 60

(CDCl₃) δ: 7.84 (1H, d, J = 7.5 Hz), 7.68-7.59 (3H, m), 7.48 (1H, d, J =1.1 Hz), 7.44- 7.37 (2H, m), 7.32-7.14 (9H, m), 7.12-7.05 (1H, m),6.80-6.73 (2H, m), 6.69 (1H, dd, J = 7.8, 1.7 Hz), 5.84 (1H, dd, J =8.8, 3.5 Hz), 4.94 (2H, s), 4.68 (1H, dd, J = 11.2, 8.8 Hz), 4.43 (1H,dd, J = 11.2, 3.5 Hz), 3.87 (3H, s), 3.22 (2H, t, J = 8.2 Hz), 2.97-2.77(1H, m), 2.92 (4H, s), 2.49-2.34 (1H, m). 61

(CDCl₃) δ: 7.91-7.83 (2H, m), 7.68-7.62 (3H, m), 7.50 (1H, d, J = 8.2Hz), 7.45-7.38 (1H, m), 7.32-7.07 (10H, m), 6.91 (1H, dd, J = 7.3, 1.7Hz), 6.84-6.75 (2H, m), 5.21-5.17 (1H, m), 4.97 (1H, d, J = 11.6 Hz),4.90 (1H, d, J = 11.6 Hz), 4.58 (2H, s), 4.21-4.01 (2H, m), 3.90 (3H,s), 3.79-3.69 (1H, m), 3.25-3.15 (1H, m), 2.97-2.79 (5H, m), 2.58-2.50(1H, m).

Reference Example 62 Methyl1-[2-(2-methoxymethoxyphenyl)ethylamino]indane-5-carboxylate

Reference Example 53 (1.08 g) was dissolved in DMF (10 mL), added underice cooling with thiophenol (0.41 mL) and potassium carbonate (553 mg)and stirred for 18 hours at room temperature. After dilution with water,extracted with diethyl ether. The organic layer was washed with waterand saturated brine in order, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure and the residues werepurified by amine silica gel column chromatography (67% ethylacetate/hexane) to obtain the title compound (638 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 7.88-7.85 (2H, m), 7.32 (1H, d, J=7.7 Hz), 7.20-7.15(2H, m), 7.08 (1H, dd, J=8.6, 1.1 Hz), 6.95 (1H, ddd, J=8.4, 7.5, 1.1Hz), 5.20 (2H, s), 4.30 (1H, t, J=7.0 Hz), 3.90 (3H, s), 3.45 (3H, s),3.05-2.77 (6H, m), 2.49-2.38 (1H, m), 1.91-1.79 (1H, m).

Compounds of Reference Examples 63 to 70, which have been produced byusing the compound of Reference Examples 54 to 61 according to the samemethod as Reference Example 62, are shown in Table 6. Meanwhile,Reference Examples 66, 67, 68 and 70 were isolated as a hydrochloridesalt.

TABLE 6 Reference Structural Example formula ¹H-NMR 63

(CDCl₃) δ: 7.77-7.75 (2H, m), 7.33 (1H, d, J = 8.6 Hz), 7.20-7.15 (2H,m), 7.09- 7.06 (1H, m), 6.97-6.92 (1H, m), 5.18 (2H, s), 3.89 (3H, s),3.82-3.80 (1H, m), 3.44 (3H, s), 3.02-2.69 (6H, m), 1.99- 1.66 (4H, m).64

(CDCl₃) δ: 7.74-7.72 (2H, m), 7.32-7.16 (12H, m), 6.93-6.88 (2H, m),5.03 (2H, s), 3.88 (3H, s), 3.78 (1H, t, J = 5.0 Hz), 3.04-2.66 (10H,m), 1.95-1.63 (4H, m). 65

(CDCl₃) δ: 7.80 (1H, dd, J = 8.0, 1.7 Hz), 7.74 (1H, d, J = 1.7 Hz),7.34 (1H, d, J = 8.0 Hz), 7.19-7.14 (2H, m), 7.07- 7.04 (1H, m), 6.93(1H, ddd, J = 8.4, 7.3, 1.1 Hz), 5.15 (2H, s), 3.91-3.88 (1H, m), 3.89(3H, s), 3.40 (3H, s), 2.94-2.71 (6H, m), 1.94-1.38 (6H, m). 66

(DMSO-D₆) δ: 7.74 (1H, d, J = 8.1 Hz), 7.47 (1H, dd, J = 8.1, 1.7 Hz),7.39-7.05 (13H, m), 6.92 (1H, t, J = 7.3 Hz), 5.07 (2H, s), 4.64-4.54(1H, m), 4.44-4.18 (2H, m), 3.82 (3H, s), 3.46-3.00 (4H, m), 2.86 (4H,s), 2.40-2.10 (2H, m). 67

(DMSO-D₆) δ: 7.71 (1H, s), 7.66-7.57 (2H, m), 7.40-7.04 (12H, m), 6.91(1H, t, J = 7.3 Hz), 5.05 (2H, s), 4.66-4.55 (1H, m), 3.82 (3H, s),3.35-2.65 (11H, m), 2.10- 1.93 (1H, m). 68

(DMSO-D₆) δ: 8.24 (1H, d, J = 7.5 Hz), 7.85 (1H, d, J = 8.1 Hz), 7.36(2H, d, J = 8.1 Hz), 7.31-7.12 (9H, m), 7.08 (1H, d, J = 8.1 Hz), 6.91(1H, t, J = 7.5 Hz), 5.07 (2H, s), 4.68-4.56 (1H, br m), 3.86 (3H, s),3.20-2.75 (6H, m), 2.87 (4H, s), 2.18-1.91 (3H, m), 1.86-1.70 (1H, m).69

(CDCl₃) δ: 7.56 (1H, dd, J = 7.7, 1.3 Hz), 7.44 (1H, d, J = 1.3 Hz),7.32-7.24 (5H, m), 7.22-7.13 (7H, m), 6.93-6.87 (2H, m), 5.02 (2H, s),4.56-4.45 (2H, m), 4.32 (1H, dd, J = 7.8, 2.5 Hz), 3.88 (3H, s),3.03-2.82 (4H, m), 2.92 (4H, s). 70

(DMSO-D₆) δ: 7.95-7.72 (3H, m), 7.30-7.14 (11H, m), 7.05 (1H, d, J = 8.2Hz), 6.90 (1H, t, J = 7.5 Hz), 5.04 (2H, s), 4.96 (1H, d, J = 15.9 Hz),4.74 (1H, d, J = 15.9 Hz), 4.55-4.44 (2H, m), 3.89-3.80 (1H, m), 3.83(3H, s), 3.20-2.95 (4H, m), 2.86 (4H, s).

Reference Example 71 Methyl1-{N-(4-Methoxycarbonylbutyl)-N-[2-(2-methoxymethoxyphenyl)ethyl]amino}indane-5-carboxylate

Reference Example 62 (636 mg) was dissolved in DMF (9.0 mL), added withpotassium carbonate (495 mg) and methyl 5-bromovalerate (0.51 mL) andheated for 18.5 hours at 95° C. After cooling to room temperature, thesolvent was evaporated under reduced pressure. The residues weresuspended in water and extracted with ethyl acetate. The organic layerwas washed with water and saturated brine in order, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure and the residues were purified by silica gel columnchromatography (17% ethyl acetate/hexane) to obtain the title compound(568 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 7.84-7.82 (2H, m), 7.27-7.24 (1H, m), 7.17-7.07 (2H,m), 7.01 (1H, dd, J=8.2, 1.0 Hz), 6.90 (1H, ddd, J=8.4, 7.3, 1.1 Hz),5.07 (2H, s), 4.57 (1H, t, J=8.0 Hz), 3.90 (3H, s), 3.66 (3H, s), 3.35(3H, s), 2.97-2.56 (6H, m), 2.52 (2H, t, J=6.9 Hz), 2.29 (2H, t, J=7.2Hz), 2.23-2.13 (1H, m), 2.02-1.89 (1H, m), 1.74-1.48 (4H, m).

Compounds of Reference Examples 72 to 81, which have been produced byusing the compound of Reference Example 50 and Reference Examples 63 to70 according to the same method as Reference Example 71, are shown inTable 7 and Table 8.

TABLE 7 Reference Structural Example formula ¹H-NMR 72

(CDCl₃) δ: 7.75-7.70 (3H, m), 7.16-7.06 (2H, m), 7.00 (1H, dd, J = 8.3,0.9 Hz), 6.89 (1H, ddd, J = 8.6, 7.3, 1.3 Hz), 5.04 (2H, s), 3.98 (1H,dd, J = 9.5, 4.8 Hz), 3.90 (3H, s), 3.66 (3H, s), 3.34 (3H, s),2.86-2.50 (8H, m), 2.29 (2H, t, J = 7.3 Hz), 2.09-1.97 (2H, m), 1.76-1.46 (6H, m). 73

(CDCl₃) δ: 7.71-7.64 (3H, m), 7.31-7.08 (11H, m), 6.91-6.85 (2H, m),4.93 (2H, s), 3.98-3.92 (1H, m), 3.88 (3H, s), 3.63 (3H, s), 2.92-2.85(6H, m), 2.76- 2.63 (6H, m), 2.43 (2H, t, J = 7.1 Hz), 2.20 (2H, t, J =7.3 Hz), 2.00-1.90 (2H, m), 1.62-1.37 (4H, m). 74

(CDCl₃) δ: 7.79 (1H, dd, J = 7.9, 1.8 Hz), 7.75-7.72 (1H, m), 7.35 (1H,d, J = 7.9 Hz), 7.15-7.10 (1H, m), 7.04-7.00 (2H, m), 6.88 (1H, ddd, J =8.6, 7.4, 1.3 Hz), 5.14 (1H, d, J = 6.8 Hz), 5.11 (1H, d, J = 6.8 Hz),4.20-4.13 (1H, m), 3.90 (3H, s), 3.65 (3H, s), 3.42 (3H, s), 2.81-2.47(7H, m), 2.39-2.33 (1H, m), 2.29 (2H, t, J = 7.1 Hz), 1.90-1.53 (10H,m). 75

(CDCl₃) δ: 8.05 (1H, s), 7.51-7.43 (2H, m), 7.39 (1H, d, J = 1.6 Hz),7.32-7.08 (10H, m), 6.91-6.85 (2H, m), 4.93 (2H, s), 4.21-4.14 (2H, m),4.07 (1H, t, J = 8.0 Hz), 3.87 (3H, s), 3.64 (3H, s), 2.96-2.83 (5H, m),2.78-2.55 (3H, m), 2.50-2.30 (4H, m), 2.20 (2H, t, J = 7.3 Hz),1.95-1.85 (2H, m), 1.76- 1.35 (2H, m). 76

(DMSO-D₆) δ: 8.16 (1H, s), 7.61-7.55 (2H, m), 7.48 (1H, dd, J = 8.2, 1.8Hz), 7.29-7.07 (10H, m), 6.98 (1H, d, J = 7.4 Hz), 6.84 (1H, ddd, J =8.7, 7.4, 1.2 Hz), 4.98 (2H, s), 3.96-3.89 (1H, m), 3.82 (3H, s), 3.56(3H, s), 3.10-2.87 (5H, m), 2.81-2.62 (4H, m), 1.99-1.85 (1H, m),1.71-1.55 (6H, m), 1.54-1.34 (4H, m). 77

(CDCl₃) δ: 7.92 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 8.1 Hz), 7.32-7.24(2H, m), 7.24-7.13 (8H, m), 7.08 (1H, dd, J = 7.6, 1.4 Hz), 6.92-6.84(2H, m), 4.91 (2H, s), 4.00-3.93 (1H, m), 3.96 (3H, s), 3.64 (3H, s),3.06-2.81 (3H, m), 2.92 (4H, s), 2.78-2.59 (3H, m), 2.51- 2.35 (2H, m),2.21 (2H, t, J = 7.2 Hz), 2.06-1.97 (2H, m), 1.69-1.35 (6H, m).

TABLE 8 78

(CDCl₃) δ: 7.52 (1H, dd, J = 7.8, 1.3 Hz), 7.38 (1H, d, J = 1.3 Hz),7.32-7.23 (4H, m), 7.22-7.13 (7H, m), 7.09 (1H, dd, J = 7.6, 1.3 Hz),6.91- 6.84 (2H, m), 4.98 (2H, s), 4.69 (1H, dd, J = 8.6, 4.6 Hz),4.42-4.30 (2H, m), 3.87 (3H, s), 3.64 (3H, s), 2.94- 2.60 (4H, m), 2.90(4H, s), 2.49-2.37 (1H, m), 2.37-2.25 (1H, m), 2.17 (2H, t, J = 7.5 Hz),1.57-1.31 (4H, m). 79

(DMSO-D₆) δ: 7.70 (1H, dd, J = 8.1, 1.8 Hz), 7.61 (1H, d, J = 1.8 Hz),7.47 (1H, d, J = 8.1 Hz), 7.27-7.06 (11H, m), 6.96 (1H, dd, J = 8.1, 0.9Hz), 6.83 (1H, ddd, J = 8.5, 7.4, 0.9 Hz), 4.99 (1H, d, J = 12.5 Hz),4.94 (1H, d, J = 12.5 Hz), 4.69 (1H, d, J = 15.5 Hz), 4.58 (1H, d, J =15.5 Hz), 3.94-3.81 (3H, m), 3.83 (3H, s), 3.56 (3H, s), 2.89 (4H, s),2.80-2.49 (6H, m), 2.15 (2H, t, J = 7.1 Hz), 1.55-1.32 (4H, m). 80

(DMSO-D₆) δ: 7.71 (1H, d, J = 8.4 Hz), 7.61-7.58 (2H, m), 7.28-7.02(13H, m), 4.11-3.98 (1H, m), 4.01 (2H, q, J = 7.1 Hz), 3.80 (3H, s),2.83-2.33 (14H, m), 2.24 (2H, t, J = 6.9 Hz), 2.05-1.85 (2H, m), 1.59-1.47 (8H, m), 1.13 (3H, t, J = 7.1 Hz). 81

(CDCl₃) δ: 7.73-7.70 (2H, m), 7.60 (1H, d, J = 7.7 Hz), 7.32-7.09 (11H,m), 6.91-6.87 (2H, m), 4.94 (2H, s), 3.98- 3.96 (1H, m), 3.88 (3H, s),2.94-2.83 (5H, m), 2.77-2.66 (5H, m), 2.47-2.33 (2H, m), 2.11 (2H, t, J= 6.9 Hz), 2.06-1.83 (4H, m), 1.61-1.42 (4H, m).

Reference Example 82 Methyl1-{N-(4-methoxycarbonylbutyl)-N-[2-(2-hydroxyphenyl)ethyl]amino}indane-5-carboxylate

Reference Example 71 (564 mg) was dissolved in THF (5.5 mL) and methanol(0.5 mL), added with conc. hydrochloric acid (0.6 mL) and stirred for 22hours at room temperature. The solvent was evaporated under reducedpressure, and the residues were diluted with water and adjusted to pH 8using a saturated aqueous solution of sodium hydrogen carbonate underice cooling. After extraction with ethyl acetate, the organic layer waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residues werepurified by silica gel column chromatography (20% ethyl acetate/hexane)to obtain the title compound (304 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 12.19 (1H, s), 7.86-7.81 (2H, m), 7.53 (1H, d, J=8.1Hz), 7.14 (1H, ddd, J=9.7, 8.1, 1.9 Hz), 6.96-6.91 (2H, m), 6.74 (1H,ddd, J=8.4, 7.2, 1.3 Hz), 4.76 (1H, t, J=7.4 Hz), 3.89 (3H, s), 3.62(3H, s), 3.04-2.54 (7H, m), 2.43-2.22 (4H, m), 2.10-1.98 (1H, m),1.61-1.51 (4H, m).

Compounds of Reference Examples 83 and 84, which have been produced byusing the compound of Reference Examples 72 and 74 according to the samemethod as Reference Example 82, are shown in Table 9.

TABLE 9 Reference Example Structural formula ¹H-NMR 83

(CDCl₃) δ: 11.47 (1H, s), 7.73- 7.64 (3H, m), 7.16-7.10 (1H, m),6.93-6.90 (2H, m), 6.73 (1H, ddd, J = 8.6, 7.3, 1.3 Hz), 4.32-4.27 (1H,m), 3.88 (3H, s), 3.63 (3H, s), 2.96- 2.62 (7H, m), 2.51-2.42 (1H, m),2.27 (2H, t, J = 7.1 Hz), 2.16-2.09 (1H, m), 2.01-1.96 (1H, m),1.76-1.54 (6H, m). 84

(CDCl₃) δ: 11.25 (1H, s), 7.86 (1H, d, J = 8.1 Hz), 7.79 (1H, d, J = 1.8Hz), 7.30-7.25 (1H, m), 7.14-7.08 (1H, m), 6.97- 6.96 (1H, m), 6.85 (1H,d, J = 8.1 Hz), 6.77-6.72 (1H, m), 4.14 (1H, t, J = 8.6 Hz), 3.90 (3H,s), 3.64 (3H, s), 3.08- 2.59 (8H, m), 2.28 (2H, t, J = 6.9 Hz),2.06-1.38 (10H, m).

Reference Example 85 Methyl1-{N-(4-methoxycarbonylbutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}indane-5-carboxylate

Reference Example 82 (298 mg) was dissolved in acetonitrile (2.8 mL),added with 4-(2-phenylethyl)benzyl chloride (194 mg) and potassiumcarbonate (145 mg), and stirred for 18 hours under reflux with heating.After cooling to room temperature, the solvent was evaporated underreduced pressure and the residues were suspended in water followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the residues were purified bysilica gel column chromatography (17% ethyl acetate/hexane) to obtainthe title compound (393 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 7.81-7.78 (2H, m), 7.31-7.09 (12H, m), 6.90-6.85 (2H,m), 4.97 (1H, d, J=13.2 Hz), 4.93 (1H, d, J=13.2 Hz), 4.51 (1H, t, J=8.1Hz), 3.88 (3H, s), 3.64 (3H, s), 2.94-2.82 (6H, m), 2.76-2.59 (4H, m),2.42 (2H, t, J=6.9 Hz), 2.21 (2H, t, J=7.3 Hz), 2.14-2.06 (1H, m),1.97-1.84 (1H, m), 1.65-1.39 (4H, m).

Compounds of Reference Examples 86 to 108, which have been produced byusing the corresponding compound (13) and the compound of ReferenceExample 83 or 84 according to the same method as Reference Example 85,are shown in Table 10 to Table 13.

TABLE 10 Reference Example Structural formula ¹H-NMR 86

(CDCl₃) δ: 7.72-7.64 (3H, m), 7.32-7.08 (11H, m), 6.90-6.85 (2H, m),4.92 (2H, s), 3.98-3.93 (1H, m), 3.88 (3H, s), 3.63 (3H, s), 2.92-2.85(5H, m), 2.76-2.58 (5H, m), 2.43 (2H, t, J = 6.9 Hz), 2.20 (2H, t, J =7.4 Hz), 2.02-1.89 (2H, m), 1.64-1.36 (6H, m). 87

(CDCl₃) δ: 7.76-7.71 (2H, m), 7.31-7.11 (11H, m), 7.03 (1H, d, J = 6.6Hz), 6.88- 6.83 (2H, m), 4.99 (2H, s), 3.88 (3H, s), 3.82-3.80 (1H, m),3.62 (3H, s), 3.22-3.15 (1H, m), 2.92-2.70 (9H, m), 2.60-2.42 (3H, m),2.17 (2H, t, J = 7.1 Hz), 1.98-1.38 (9H, m). 88

(CDCl₃) δ: 7.68-7.60 (3H, m), 7.30-7.08 (11H, m), 6.91-6.81 (2H, m),4.88 (1H, d, J = 11.5 Hz), 4.84 (1H, d, J = 11.5 Hz), 3.93-3.91 (1H, m),3.88 (3H, s), 3.63 (3H, s), 2.98-2.82 (5H, m), 2.69-2.57 (5H, m), 2.37(2H, t, J = 6.8 Hz), 2.16 (2H, t, J = 7.4 Hz), 1.91-1.86 (2H, m),1.60-1.31 (6H, m). 89

(CDCl₃) δ: 7.70-7.63 (3H, m), 7.30-7.08 (11H, m), 6.90-6.84 (2H, m),4.92 (2H, s), 3.94-3.92 (1H, m), 3.87 (3H, s), 3.63 (3H, s), 2.93-2.86(5H, m), 2.73-2.62 (5H, m), 2.43 (2H, t, J = 7.0 Hz), 2.18 (2H, t, J =7.4 Hz), 2.01-1.88 (2H, m), 1.63-1.36 (6H, m). 90

(CDCl₃) δ: 7.72-7.63 (3H, m), 7.38-7.28 (5H, m), 7.19-7.12 (1H, m), 7.10(1H, dd, J = 7.5, 1.3 Hz), 6.90- 6.84 (2H, m), 4.95 (2H, s), 4.00-3.91(1H, br m), 3.88 (3H, s), 3.64 (3H, s), 2.95- 2.83 (1H, m), 2.79- 2.55(5H, m), 2.44 (2H, t, J = 7.0 Hz), 2.20 (2H, t, J = 7.3 Hz), 2.03-1.87(2H, m), 1.67-1.35 (6H, m). 91

(CDCl₃) δ: 7.69-7.64 (3H, m), 7.42-7.36 (2H, m), 7.28-7.20 (2H, m),7.19-7.09 (2H, m), 6.93-6.82 (2H, m), 5.05 (2H, s), 3.98- 3.93 (1H, m),3.88 (3H, s), 3.64 (3H, s), 2.96-2.87 (1H, m), 2.79- 2.62 (5H, m), 2.47(2H, t, J = 6.9 Hz), 2.22 (2H, t, J = 7.4 Hz), 2.04-1.92 (2H, m),1.64-1.38 (6H, m). 92

(CDCl₃) δ: 7.75-7.61 (3H, m), 7.48-7.19 (6H, m), 7.18-7.12 (1H, m), 7.09(1H, dd, J = 7.7, 1.9 Hz), 6.99- 6.81 (5H, m), 5.06 (2H, s), 4.88 (2H,s), 3.98-3.86 (1H, m), 3.88 (3H, s), 3.63 (3H, s), 2.94-2.80 (1H, m),2.79-2.56 (5H, m), 2.42 (2H, t, J= 6.8 Hz), 2.20 (2H, t, J = 7.4 Hz),2.02- 1.86 (2H, m), 1.61-1.33 (6H, m).

TABLE 11 93

(CDCl₃) δ: 7.73-7.60 (3H, m), 7.35-7.05 (11H, m), 6.87 (1H, ddd, J =8.3, 7.5, 1.1 Hz), 6.82 (1H, d, J = 8.3 Hz), 4.89 (2H, s), 4.12 (2H, s),3.97-3.92 (1H, m), 3.88 (3H, s), 3.64 (3H, s), 2.93-2.80 (1H, m),2.78-2.53 (5H, m), 2.44 (2H, t, J = 7.0 Hz), 2.21 (2H, t, J = 7.3 Hz),2.03-1.87 (2H, m), 1.67-1.34 (6H, m). 94

(CDCl₃) δ: 7.72-7.62 (3H, m), 7.40 (2H, d, J = 8.2 Hz), 7.35-7.25 (4H,m), 7.15 (1H, ddd, J = 9.3, 7.5, 1.6 Hz), 7.10 (1H, dd, J = 7.5, 1.6Hz), 7.01-6.82 (5H, m), 5.06 (2H, s), 4.96 (2H, s), 3.99-3.90 (1H, m),3.87 (3H, s), 3.63 (3H, s), 2.95-2.82 (1H, m), 2.79-2.55 (5H, m), 2.44(2H, t, J = 7.0 Hz), 2.20 (2H, t, J = 7.4 Hz), 2.03- 1.87 (2H, m),1.65-1.35 (6H, m). 95

(CDCl₃) δ: 7.71-7.61 (3H, m), 7.35-7.07 (11H, m), 6.91-6.80 (2H, m),4.91 (2H, s), 4.12 (2H, s), 3.96-3.88 (1H, m), 3.88 (3H, s), 3.64 (3H,s), 2.93-2.82 (1H, m), 2.77- 2.58 (5H, m), 2.43 (2H, t, J = 7.0 Hz),2.20 (2H, t, J = 7.0 Hz), 2.03-1.87 (2H, m), 1.66-1.35 (6H, m). 96

(CDCl₃) δ: 7.68-7.60 (5H, m), 7.54-7.43 (2H, m), 7.26-7.07 (11H, m),6.89-6.79 (2H, m), 4.96 (2H, s), 4.89 (2H, s), 3.97- 3.90 (1H, m), 3.88(3H, s), 3.64 (3H, s), 2.91-2.82 (1H, m), 2.70-2.59 (5H, m), 2.43 (2H,t, J = 6.9 Hz), 2.19 (2H, t, J = 7.3 Hz), 1.99-1.90 (2H, m), 1.61-1.37(6H, m). 97

(CDCl₃) δ: 7.71-7.60 (3H, m), 7.45 (2H, d, J = 8.2 Hz), 7.29-7.22 (2H,m), 7.19-7.07 (2H, m), 6.88 (1H, ddd, J = 8.3, 7.3, 0.9 Hz), 6.81 (1H,d, J = 8.0 Hz), 4.94 (2H, s), 3.99-3.91 (1H, m), 3.88 (3H, s), 3.65 (3H,s), 3.08 (1H, s), 2.93-2.80 (1H, m), 2.79-2.55 (5H, m), 2.46 (2H, t, J =6.9 Hz), 2.22 (2H, t, J = 7.3 Hz), 2.02-1.90 (2H, m), 1.69-1.36 (6H, m).98

(CDCl₃) δ: 7.71-7.61 (3H, m), 7.34 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J =8.1 Hz), 7.18-7.07 (2H, m), 6.87 (1H, ddd, J = 8.0, 7.4, 0.8 Hz), 6.81(1H, d, J = 8.0 Hz), 4.91 (2H, s), 3.98-3.90 (1H, m), 3.88 (3H, s), 3.65(3H, s), 2.93-2.57 (7H, m), 2.45 (2H, t, J = 6.9 Hz), 2.22 (2H, t, J =7.4 Hz), 2.02-1.90 (2H, m), 1.68-1.36 (6H, m), 1.27 (6H, d, J = 6.6 Hz).

TABLE 12  99

(CDCl₃) δ: 7.71-7.61 (3H, m), 7.33 (2H, d, J = 8.3 Hz), 7.19 (2H, d, J =8.3 Hz), 7.17-7.07 (2H, m), 6.87 (1H, ddd, J = 8.3, 7.5, 0.9 Hz), 6.81(1H, d, J = 8.3 Hz), 4.91 (2H, s), 3.98-3.90 (1H, m), 3.88 (3H, s), 3.65(3H, s), 2.93-2.81 (1H, m), 2.78- 2.54 (5H, m), 2.44 (2H, t, J = 7.0Hz), 2.22 (2H, t, J = 7.5 Hz), 2.02-1.89 (2H, m), 1.68-1.34 (7H, m),0.91-0.78 (4H, m). 100

(CDCl₃) δ: 7.71-7.60 (3H, m), 7.35 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J =8.3 Hz), 7.17-7.07 (2H, m), 6.87 (1H, ddd, J = 8.3, 7.5, 1.0 Hz), 6.81(1H, dd, J = 8.3, 0.8 Hz), 4.91 (2H, s), 3.99-3.91 (1H, m), 3.88 (3H,s), 3.65 (3H, s), 2.94-2.80 (1H, m), 2.78-2.52 (5H, m), 2.44 (2H, t, J =6.9 Hz), 2.22 (2H, t, J = 7.4 Hz), 2.02-1.83 (4H, m), 1.82-1.69 (2H, m),1.65-1.30 (13H, m). 101

(CDCl₃) δ: 7.72-7.63 (3H, m), 7.33-7.19 (4H, m), 7.17-7.07 (2H, m),6.89-6.82 (2H, m), 6.33 (1H, d, J = 15.9 Hz), 6.17 (1H, dd, J = 15.9,6.8 Hz), 4.92 (2H, s), 3.98- 3.87 (1H, m), 3.88 (3H, s), 3.64 (3H, s),2.95-2.82 (1H, m), 2.78-2.55 (5H, m), 2.43 (2H, t, J = 6.9 Hz),2.23-2.08 (1H, m), 2.20 (2H, t, J = 7.3 Hz), 2.01-1.87 (2H, m),1.86-1.09 (16H, m). 102

(CDCl₃) δ: 7.72-7.63 (3H, m), 7.28-7.07 (6H, m), 6.90-6.83 (2H, m), 4.91(2H, s), 3.99-3.91 (1H, m), 3.88 (3H, s), 3.64 (3H, s), 2.96-2.83 (1H,m), 2.76-2.56 (7H, m), 2.42 (2H, t, J = 6.9 Hz), 2.20 (2H, t, J = 7.3Hz), 2.02-1.86 (2H, m), 1.83-1.35 (13H, m), 1.33-1.11 (4H, m), 1.02-0.86(2H, m). 103

(CDCl₃) δ: 7.72-7.62 (3H, m), 7.18-7.12 (1H, m), 7.09 (1H, dd, J = 7.7,1.8 Hz), 7.04-6.98 (3H, m), 6.90-6.82 (2H, m), 4.87 (2H, s), 3.99-3.91(1H, m), 3.88 (3H, s), 3.64 (3H, s), 2.95-2.83 (1H, m), 2.79-2.59 (9H,m), 2.43 (2H, t, J = 6.9 Hz), 2.19 (2H, t, J = 7.5 Hz), 2.02-1.87 (2H,m), 1.82-1.75 (4H, m), 1.65-1.35 (6H, m). 104

(CDCl₃) δ: 7.73-7.61 (3H, m), 7.22-7.01 (5H, m), 6.93-6.83 (2H, m), 4.90(2H, s), 3.97-3.86 (1H, m), 3.89 (3H, s), 3.64 (3H, s), 2.96-2.56 (10H,m), 2.40 (2H, t, J = 7.0 Hz), 2.18 (2H, t, J = 7.3 Hz), 2.00- 1.70 (6H,m), 1.63-1.32 (6H, m).

TABLE 13 105

(CDCl₃) δ: 7.72-7.62 (3H, m), 7.15 (1H, ddd, J = 9.4, 7.7, 1.7 Hz), 7.08(1H, dd, J = 7.2, 1.7 Hz), 6.89-6.74 (5H, m), 4.83 (2H, s), 4.25 (4H,s), 4.00-3.91 (1H, m), 3.88 (3H, s), 3.64 (3H, s), 2.93- 2.81 (1H, m),2.78-2.57 (5H, m), 2.44 (2H, t, J = 6.8 Hz), 2.21 (2H, t, J = 7.3 Hz),2.06-1.89 (2H, m), 1.61-1.36 (6H, m). 106

(CDCl₃) δ: 7.73-7.61 (3H, m), 7.19-7.12 (1H, m), 7.09 (1H, dd, J = 7.8,1.9 Hz), 7.05- 6.95 (2H, m), 6.90-6.82 (2H, m), 6.75 (1H, d, J = 7.7 Hz)4.82 (2H, s), 4.20-4.15 (2H, m), 3.98-3.91 (1H, m), 3.88 (3H, s), 3.64(3H, s), 2.92- 2.57 (8H, m), 2.42 (2H, t, J = 6.9 Hz), 2.19 (2H, t, J =7.2 Hz), 2.05-1.88 (4H, m), 1.63 1.34 (6H, m). 107

(CDCl₃) δ: 7.72-7.61 (3H, m), 7.15 (1H, ddd, J = 9.5, 7.7, 1.7 Hz), 7.09(1H, dd, J = 7.3, 1.7 Hz), 7.06-6.93 (3H, m), 6.90-6.81 (2H, m), 4.83(2H, s), 3.99-3.90 (1H, m), 3.88 (3H, s), 3.64 (3H, s), 3.06-2.95 (2H,m), 2.93-2.80 (1H, m), 2.79-2.57 (7H, m), 2.43 (2H, t, J = 7.0 Hz), 2.20(2H, t, J = 7.3 Hz), 2.15-2.05 (2H, m), 2.02-1.87 (2H, m), 1.66-1.33(6H, m). 108

(CDCl₃) δ: 7.73-7.61 (3H, m), 7.15 (1H, ddd, J = 9.4, 7.5, 1.7 Hz), 7.09(1H, dd, J = 7.5, 1.7 Hz), 6.91-6.81 (2H, m), 6.78-6.74 (3H, m), 5.96(2H, s), 4.84 (2H, s), 4.01- 3.91 (1H, m), 3.88 (3H, s), 3.64 (3H, s),2.93-2.80 (1H, m), 2.77-2.56 (5H, m), 2.45 (2H, t, J = 7.0 Hz), 2.21(2H, t, J = 7.3 Hz), 2.07-1.90 (2H, m), 1.68-1.36 (6H, m).

Reference Example 109 Methyl5-{N-(4-methoxycarbonylbutyl)-N-[2-[2-[trans-4-((E)-2-phenylvinyl)cyclohexylmethoxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylate

According to the same method as Reference Example 53, the title compound(132 mg) was obtained as a yellow oil from Reference Example 83 (175 mg)and Reference Example 28 (95.0 mg).

¹H-NMR (CDCl3) δ: 7.76-7.63 (3H, m), 7.39-7.23 (4H, m), 7.23-7.10 (2H,m), 7.07 (1H, dd, J=7.3, 1.6 Hz), 6.84 (1H, ddd, J=8.4, 7.3, 1.1 Hz),6.77 (1H, dd, J=8.3, 1.1 Hz), 6.37 (1H, d, J=16.1 Hz), 6.17 (1H, dd,J=16.1, 7.0 Hz), 4.05-3.95 (1H, m), 3.89 (3H, s), 3.73-3.65 (2H, m),3.64 (3H, s), 2.94-2.59 (6H, m), 2.51 (2H, t, J=7.0 Hz), 2.27 (2H, t,J=7.5 Hz), 2.15-1.95 (3H, m), 1.95-1.83 (3H, m), 1.76-1.38 (8H, m),1.33-1.03 (4H, m).

Compounds of Reference Examples 110 to 115, which have been produced byusing the corresponding compound (13) and the compound of ReferenceExample 83 according to the same method as Reference Example 109, areshown in Table 14.

TABLE 14 Reference Example Structural formula ¹H-NMR 110

(CDCl₃) δ: 7.74-7.64 (3H, m), 7.32-7.23 (2H, m), 7.22-7.09 (4H, m), 7.06(1H, dd, J = 7.5, 1.5 Hz), 6.83 (1H, ddd, J = 8.2, 7.5, 0.9 Hz), 6.76(1H, dd, J = 8.2, 0.8 Hz), 4.03-3.95 (1H, m), 3.88 (3H, s), 3.67- 3.62(2H, m), 3.64 (3H, s), 2.93-2.58 (8H, m), 2.50 (2H, t, J = 7.0 Hz), 2.26(2H, t, J = 7.1 Hz), 2.10-1.95 (2H, m), 1.89-1.79 (2H, m), 1.72-1.41(12H, m), 1.08-0.92 (4H, m). 111

(CDCl₃) δ: 7.73-7.61 (3H, m), 7.31-7.23 (2H, m), 7.21-7.11 (4H, m), 7.06(1H, dd, J = 7.3, 1.8 Hz), 6.83 (1H, ddd, J = 8.5, 7.3, 1.0 Hz), 6.78(1H, dd, J = 8.3, 1.0 Hz), 4.02-3.94 (1H, m), 3.87 (3H, s), 3.80- 3.68(2H, m), 3.65 (3H, s), 2.91-2.54 (8H, m), 2.49 (2H, t, J = 7.0 Hz), 2.26(2H, t, J = 7.3 Hz), 2.13- 1.94 (3H, br m), 1.93- 1.79 (1H, br m),1.74-1.21 (16H, m). 112

(CDCl₃) δ: 7.76-7.63 (3H, m), 7.20-7.12 (1H, m), 7.09 (1H, dd, J = 7.5,1.3 Hz), 6.92-6.83 (2H, m), 6.61 (1H, s), 5.02 (1H, d, J = 11.8 Hz),4.97 (1H, d, J = 11.8 Hz), 4.02-3.93 (1H, m), 3.89 (3H, s), 3.64 (3H,s), 2.80-2.49 (10H, m), 2.43 (2H, t, J = 6.8 Hz), 2.21 (2H, t, J = 7.2Hz), 2.10- 1.90 (2H, m), 1.89- 1.71 (5H, m), 1.69-1.35 (5H, m). 113

(CDCl₃) δ: 7.76-7.62 (4H, m), 7.19-7.01 (4H, m), 6.89-6.73 (3H, m),4.04-3.95 (1H, m), 3.90-3.81 (2H, m), 3.89 (3H, s), 3.65 (3H, s),2.92-2.43 (12H, m), 2.27 (2H, t, J = 7.4 Hz), 2.12-1.94 (4H, m),1.74-1.35 (7H, m). 114

(CDCl₃) δ: 7.68-7.59 (3H, m), 7.32-6.84 (12H, m), 5.31-5.29 (1H, m),3.88 (3H, s), 3.85-3.83 (1H, m), 3.64, 3.62 (3H, each s), 2.90-2.48(13H, m), 2.38-2.32 (2H, m), 2.21-2.13 (2H, m), 1.95-1.35 (11H, m). 115

(CDCl₃) δ: 7.75-7.67 (3H, m), 7.42-7.36 (2H, m), 7.33-7.27 (3H, m), 7.18(1H, ddd, J = 8.0, 7.5, 1.7 Hz), 7.09 (1H, dd, J = 7.5, 1.7 Hz), 6.99(1H, d, J = 8.0 Hz), 6.89 (1H, ddd, J = 8.4, 7.5, 1.1 Hz), 4.81 (2H, s),4.05-3.96 (1H, m), 3.88 (3H, s), 3.64 (3H, s), 2.94-2.82 (1H, m),2.80-2.59 (5H, m), 2.50 (2H, t, J = 6.7 Hz), 2.24 (2H, t, J = 7.3 Hz),2.11-1.90 (2H, m), 1.73-1.41 (6H, m).

Reference Example 116 Methyl5-{N-(4-methoxycarbonylbutyl)-N-[2-[2-[4-(2-phenylaminomethyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylate

According to the same method as Reference Example 62, the title compoundwas obtained as a yellow oil from Reference Example 96 (172 mg).

¹H-NMR (CDCl3) δ: 7.69-7.60 (3H, m), 7.35-7.08 (8H, m), 6.89-6.84 (2H,m), 6.74-6.64 (3H, m), 4.94 (2H, s), 4.33 (2H, s), 3.97-3.91 (1H, m),3.87 (3H, s), 3.64 (3H, s), 2.90-2.60 (6H, m), 2.44 (2H, t, J=7.0 Hz),2.19 (2H, t, J=7.3 Hz), 2.00-1.91 (2H, m), 1.63-1.38 (7H, m).

Reference Example 117 Methyl5-{N-[4-(1H-tetrazol-5-yl)butyl]-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylate

Reference Example 81 (102 mg) was suspended in toluene (5.0 mL), addedwith trimethyl tin azide (175 mg), and stirred for 44 hours under refluxwith heating. After cooling to room temperature, the solvent wasevaporated under reduced pressure. The residues were dissolved inmethanol (2 mL) and stirred for 15 minutes at room temperature.Subsequently, the solvent was evaporated under reduced pressure, and theresidues were purified by silica gel column chromatography (2%methanol/chloroform) to obtain the title compound (84 mg) as yellowamorphous.

¹H-NMR (CDCl3) δ: 7.70-7.69 (3H, m), 7.30-7.06 (11H, m), 6.91-6.83 (2H,m), 4.92 (2H, s), 4.26 (1H, dd, J=8.8, 5.9 Hz), 4.11 (1H, s), 3.87 (3H,s), 2.98-2.69 (12H, m), 2.54 (2H, t, J=6.1 Hz), 2.02-1.84 (2H, m),1.75-1.48 (6H, m).

Reference Example 118 8-Oxo-5,6,7,8-tetrahydroisoquinoline-3-yltrifluoromethanesulfonate

According to the same method as Reference Example 10, the title compound(1.53 g) was obtained as a yellow oil from5,6,7,8-tetrahydroisoquinoline-3,8-dione (970 mg).

¹H-NMR (CDCl3) δ: 8.96 (1H, s), 7.07 (1H, s), 3.05 (2H, t, J=6.1 Hz),2.76-2.70 (2H, m), 2.26-2.16 (2H, m).

Reference Example 119 3-Cyano-8-oxo-5,6,7,8-tetrahydroisoquinoline

Reference Example 118 (1.53 g) was dissolved in DMF (12 mL), added withzinc cyanide (487 mg) and tetrakis(triphenylphosphine)palladium (0) (299mg) under argon atmosphere, and stirred for 3 hours at 80° C. Afterfiltration through Celite, it was diluted with ethyl acetate and washedwith saturated brine. After drying over anhydrous sodium sulfate, thesolvent was evaporated under reduced pressure and the residues werepurified by silica gel column chromatography (8 to 16% ethylacetate/hexane), suspended in a mixture solvent of hexane/diisopropylether, and collected by filtration to obtain the title compound (680 mg)as a white powder.

¹H-NMR (CDCl₃) δ: 9.20 (1H, s), 7.64-7.62 (1H, m), 3.03 (2H, t, J=6.0Hz), 2.79-2.72 (2H, m), 2.28-2.18 (2H, m).

Reference Example 120 8-Oxo-5,6,7,8-tetrahydroisoquinoline-3-carboxylicacid

According to the same method as Reference Example 8, the title compound(685 mg) was obtained as a white powder from Reference Example 119 (672mg).

¹H-NMR (CDCl₃) δ: 9.14 (1H, s), 8.15 (1H, s), 3.10 (2H, t, J=6.0 Hz),2.81-2.73 (2H, m), 2.29-2.19 (2H, m).

Reference Example 121 Methyl8-oxo-5,6,7,8-tetrahydroisoquinoline-3-carboxylate

Reference Example 120 (540 mg) was dissolved in chloroform (14 mL), andadded under ice cooling with a diethyl ether solution of diazomethaneuntil the completion of the reaction. Acetic acid was added until thereaction solution becomes colorless, and the solvent was evaporatedunder reduced pressure. The residues were purified by silica gel columnchromatography (8 to 80% ethyl acetate/hexane) to obtain the titlecompound (360 mg) as a white powder.

¹H-NMR (CDCl₃) δ: 9.24 (1H, s), 8.06-8.04 (1H, m), 4.03 (3H, s), 3.05(2H, t, J=6.1 Hz), 2.78-2.70 (2H, m), 2.27-2.16 (2H, m).

Reference Example 122 Methyl8-hydroxy-5,6,7,8-tetrahydroisoquinoline-3-carboxylate

According to the same method as Reference Example 11, the title compound(448 mg) was quantitatively obtained from Reference Example 121 (432mg).

¹H-NMR (CDCl₃) δ: 8.78 (1H, s), 7.88 (1H, s), 4.96-4.86 (1H, m), 4.00(3H, s), 2.96-2.70 (2H, m), 2.15-1.76 (5H, m).

Compounds of Reference Examples 123 and 124, which have been produced byusing the corresponding compound (4) and the compound of ReferenceExample 51 according to the same method as Reference Example 53, areshown in Table 15.

TABLE 15 Reference Example Structural formula ¹H-NMR 123

(CDCl₃) δ: 8.23-8.20 (1H, m), 7.80-7.65 (3H, m), 7.47-7.43 (2H, m), 7.20(1H, dd, J = 8.6, 1.1 Hz), 7.13 (1H, ddd, J = 9.3, 8.3, 1.7 Hz),7.04-6.95 (2H, m), 6.87 (1H, ddd, J = 8.3, 7.3, 1.1 Hz), 5.43 (1H, dd, J= 10.8, 6.0 Hz), 5.08 (1H, d, J = 6.8 Hz), 5.02 (1H, d, J = 6.8 Hz),4.44 (1H, dt, J = 11.5, 3.7 Hz), 4.27 (1H, td, J = 11.5, 2.1 Hz), 3.87(3H, s), 3.57-3.43 (1H, m), 3.28 (3H, s), 3.21-3.08 (1H, m), 2.90-2.72(2H, m), 2.55- 2.26 (2H, m). 124

(CDCl3) δ: 8.45 (1H, s), 8.21- 8.15 (1H, m), 7.86 (1H, s), 7.77-7.64(3H, m), 7.18-7.09 (1H, m), 7.04 (1H, dd, J = 7.4, 1.6 Hz), 6.96 (1H, d,J = 8.2 Hz), 6.88 (1H, ddd, J = 8.2, 7.4, 1.1 Hz), 5.36 (1H, dd, J =10.1, 5.9 Hz), 5.04 (1H, d, J = 6.8 Hz), 5.02 (1H, d, J = 6.8 Hz), 3.96(3H, s), 3.58-3.41 (1H, m), 3.31 (3H, s), 3.27-3.13 (1H, m), 3.00- 2.76(4H, m), 2.42-2.28 (1H, m), 2.20-1.83 (3H, m).

Compounds of Reference Examples 125 and 126, which have been produced byusing the compound of Reference Examples 123 and 124 according to thesame method as Reference Example 62, are shown in Table 16.

TABLE 16 Reference Example Structural formula ¹H-NMR 125

(CDCl₃) δ: 7.53-7.44 (2H, m), 7.23- 7.16 (3H, m), 7.08 (1H, dd, J = 8.7,1.2 Hz), 6.95 (1H, ddd, J = 8.6, 7.4, 1.2 Hz), 5.19 (2H, s), 4.34-4.16(2H, m), 3.88 (3H, s), 3.83 (1H, t, J = 4.6 Hz), 3.44 (3H, s), 3.02-2.84(4H, m), 2.10-1.90 (2H, m). 126

(CDCl₃) δ: 8.63 (1H, s), 7.84 (1H, s), 7.21-7.13 (2H, m), 7.09-7.04 (1H,m), 6.97-6.90 (1H, m), 5.20 (1H, d, J = 6.8 Hz), 5.18 (1H, d, J = 6.8Hz), 3.98 (3H, s), 3.88 (1H, t, J = 4.9 Hz), 3.45 (3H, s), 3.05- 2.67(6H, m), 2.05-1.81 (3H, m), 1.81-1.69 (1H, m).

Compounds of Reference Examples 127 and 128, which have been produced byusing the compound of Reference Examples 125 and 126 according to thesame method as Reference Example 71, are shown in Table 17.

TABLE 17 Reference Example Structural formula ¹H-NMR 127

(CDCl₃) δ: 7.56 (1H, d, J = 8.2 Hz), 7.49 (1H, dd, J = 8.2, 1.6 Hz),7.40 (1H, d, J = 1.6 Hz), 7.18-6.97 (3H, m), 6.90 (1H, ddd, J = 8.5,7.3, 1.2 Hz), 5.04 (2H, s), 4.38 (1H, td, J = 7.4, 3.7 Hz), 4.20-4.05(2H, m), 3.89 (3H, s), 3.67 (3H, s), 3.34 (3H, s), 2.90- 2.48 (6H, m),2.30 (2H, t, J = 7.3 Hz), 2.07-1.92 (2H, m), 1.76-1.44 (4H, m). 128

(CDCl₃) δ: 9.03 (1H, s), 7.80 (1H, s), 7.17-7.05 (2H, m), 7.01 (1H, dd,J = 8.2, 1.2 Hz), 6.89 (1H, ddd, J = 8.6, 7.4, 1.2 Hz), 5.09 (2H, s),4.12-4.02 (1H, m), 4.00 (3H, s), 3.65 (3H, s), 3.38 (3H, s), 2.92-2.44(8H, m), 2.28 (2H, t, J = 7.2 Hz), 2.16-1.98 (2H, m), 1.79-1.42 (6H, m).

Compounds of Reference Examples 129 and 130, which have been produced byusing the compound of Reference Examples 127 and 128 according to thesame method as Reference Example 82, are shown in Table 18.

TABLE 18 Reference Example Structural formula ¹H-NMR 129

(CDCl₃) δ: 11.03 (1H, s), 7.55 (1H, d, J = 7.8 Hz), 7.49-7.43 (2H, m),7.14 (1H, ddd, J = 9.6, 8.0, 1.7 Hz), 6.96-6.89 (2H, m), 6.75 (1H, ddd,J = 8.0, 7.6, 1.7 Hz), 4.38-4.30 (2H, m), 4.13-4.02 (1H, m), 3.88 (3H,s), 3.63 (3H, s), 2.96-2.63 (5H, m), 2.53-2.40 (1H, m), 2.27 (2H, t, J =6.9 Hz), 2.17-2.03 (2H, m), 1.68- 1.50 (4H, m). 130

(CDCl₃) δ: 10.17 (1H, br s), 8.91 (1H, s), 7.84 (1H, s), 7.14-7.06 (1H,m), 6.95 (1H, dd, J = 7.5, 1.5 Hz), 6.86 (1H, dd, J = 8.0, 1.3 Hz), 6.75(1H, ddd, J = 8.7, 7.5, 1.3 Hz), 4.30-4.22 (1H, m), 3.99 (3H, s), 3.63(3H, s), 2.93-2.85 (2H, m), 2.84-2.75 (4H, m), 2.61-2.50 (2H, m), 2.26(2H, t, J = 7.0 Hz), 2.22-2.07 (1H, m), 2.07-1.94 (1H, m), 1.82-1.66(2H, m), 1.65-1.45 (4H, m).

Compounds of Reference Examples 131 to 139, which have been produced byusing the corresponding compound (13) and the compound of ReferenceExample 82, Reference Example 83, Reference Example 129 or 130 accordingto the same method as Reference Example 85, are shown in Table 19 toTable 20.

TABLE 19 Reference Example Structural formula ¹H-NMR 131

(CDCl₃) δ: 8.94 (1H, s), 7.76 (1H, s), 7.32-7.24 (2H, m), 7.24-7.08 (9H,m), 6.90-6.83 (2H, m), 4.97 (2H, s), 4.06- 3.99 (1H, m), 3.98 (3H, s),3.62 (3H, s), 2.93-2.84 (1H, m), 2.91 (4H, s), 2.79-2.65 (5H, m),2.46-2.31 (2H, m), 2.19 (2H, t, J = 7.2 Hz), 2.07-1.88 (2H, m),1.63-1.31 (6H, m). 132

(CDCl₃) δ: 7.73-7.60 (3H, m), 7.36 (2H, d, J = 8.3 Hz), 7.28-7.08 (4H,m), 6.92-6.80 (2H, m), 4.93 (2H, s), 4.00- 3.93 (1H, m), 3.88 (3H, s),3.64 (3H, s), 2.97-2.82 (1H, m), 2.76-2.60 (5H, m), 2.42 (2H, t, J = 6.8Hz), 2.20 (2H, t, J = 7.3 Hz), 2.03-1.89 (2H, m), 1.65-1.38 (6H, m),1.32 (9H, s). 133

(CDCl₃) δ: 7.68-7.63 (3H, m), 7.37-7.25 (3H, m), 7.19-7.08 (3H, m),6.89-6.86 (2H, m), 4.98 (1H, d, J = 11.5 Hz), 4.93 (1H, d, J = 11.5 Hz),3.97-3.94 (1H, m), 3.88 (3H, s), 3.63 (3H, s), 2.93-2.89 (1H, m),2.68-2.65 (5H, m), 2.42 (2H, t, J = 6.8 Hz), 2.18 (2H, t, J = 7.3 Hz),1.98-1.90 (2H, m), 1.58- 1.37 (6H, m), 1.31 (9H, s). 134

(CDCl₃) δ: 7.71-7.64 (3H, m), 7.20-7.01 (6H, m), 6.89-6.84 (2H, m), 4.90(2H, s), 3.95-3.92 (1H, m), 3.88 (3H, s), 3.64 (3H, s), 2.90-2.85 (1H,m), 2.72- 2.57 (5H, m), 2.42 (2H, t, J = 6.9 Hz), 2.20 (2H, t, J = 7.4Hz), 2.00-1.84 (3H, m), 1.59-1.38 (6H, m), 0.99-0.93 (2H, m), 0.71-0.65(2H, m). 135

(CDCl₃) δ: 7.70-7.66 (3H, m), 7.19-7.12 (6H, m), 6.88-6.86 (2H, m), 4.92(2H, s), 3.98-3.94 (1H, m), 3.89 (3H, s), 3.65 (3H, s), 2.93-2.87 (2H,m), 2.76- 2.61 (5H, m), 2.42 (2H, t, J = 6.9 Hz), 2.20 (2H, t, J = 7.3Hz), 1.99-1.91 (2H, m), 1.61-1.40 (6H, m), 1.25 (6H, d, J = 7.0 Hz). 136

(CDCl3) δ: 7.72-7.62 (3H, m), 7.20-7.05 (5H, m), 6.90-6.83 (2H, m), 4.91(2H, s), 4.00-3.91 (1H, m), 3.88 (3H, s), 3.64 (3H, s), 2.95-2.82 (5H,m), 2.76- 2.60 (5H, m), 2.42 (2H, t, J = 7.0 Hz), 2.19 (2H, t, J = 7.4Hz), 2.13-1.87 (4H, m), 1.64-1.34 (6H, m).

TABLE 20 137

(CDCl₃) δ: 7.84-7.74 (2H, m), 7.28-6.82 (8H, m), 4.92 (1H, d, J = 11.5Hz), 4.87 (1H, d, J = 11.5 Hz), 4.51 (1H, t, J = 8.1 Hz), 3.89 (3H, s),3.64 (3H, s), 2.97-2.56 (9H, m), 2.49-2.36 (3H, m), 2.24-2.14 (2H, m),2.14-1.68 (8H, m), 1.62-1.37 (2H, m). 138

(CDCl₃) δ: 7.50-7.33 (3H, m), 7.28-6.92 (5H, m), 6.90-6.84 (2H, m), 4.87(2H, s), 4.30- 4.20 (1H, m), 4.06 (1H, t, J = 7.9 Hz), 3.96-3.82 (1H,m), 3.87 (3H, s), 3.64 (3H, s), 2.96-2.60 (9H, m), 2.46-2.31 (2H, m),2.19 (2H, t, J = 7.3 Hz), 1.95-1.70 (7H, m), 1.62- 1.32 (2H, m) 139

(CDCl₃) δ: 7.49-7.32 (9H, m), 7.30-7.07 (3H, m), 6.97-6.84 (4H, m), 5.06(2H, s), 4.88 (2H, s), 4.26 (1H, td, J = 7.5, 3.7 Hz), 4.05 (1H, t, J =7.9 Hz), 3.98-3.84 (1H, m), 3.87 (3H, s), 3.64 (3H, s), 2.92-2.80 (1H,m), 2.76-2.53 (3H, m), 2.48-2.32 (2H, m), 2.20 (2H, t, J = 7.3 Hz),1.94-1.84 (2H, m), 1.63-1.33 (4H, m).

Compounds of Reference Examples 140 and 141, which have been produced byusing the corresponding compound (13) and the compound of ReferenceExample 83 according to the same method as Reference Example 109, areshown in Table 21.

TABLE 21 Reference Example Structural formula ¹H-NMR 140

(CDCl₃) δ: 7.82-7.68 (3H, m), 7.35-7.12 (4H, m), 7.08-6.96 (2H, m),6.81-7.73 (1H, m), 6.65 (1H, dd, J = 7.3, 5.7 Hz), 5.26-5.13 (1H, m),4.07- 3.97 (1H, m), 3.89, 3.88 (3H, each s), 3.65 (3H, s), 3.00- 2.85(1H, m), 2.80-2.48 (7H, m), 2.31-2.24 (2H, m), 2.12- 1.95 (2H, m),1.74-1.44 (9H, m), 1.30, 1.28 (9H, each s). 141

(CDCl₃) δ: 7.82-7.68 (3H, m), 7.35-7.12 (4H, m), 7.08-6.96 (2H, m),6.81-6.74 (1H, m), 6.65 (1H, dd, J = 7.3, 5.5 Hz), 5.26-5.13 (1H, m),4.07- 3.97 (1H, m), 3.89, 3.88 (3H, each s), 3.65 (3H, s), 3.00- 2.85(1H, m), 2.80-2.48 (7H, m), 2.31-2.24 (2H, m), 2.12- 1.95 (2H, m),1.74-1.44 (9H, m), 1.30, 1.28 (9H, each s).

Example 11-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}indane-5-carboxylicacid

Reference Example 85 (391 mg) was dissolved in THF (1.0 mL) and methanol(2.1 mL), added with 2.5 mol/L aqueous solution of sodium hydroxide (1.0mL), and stirred for 1.5 hours at 50° C. After cooling to roomtemperature, the solvent was evaporated under reduced pressure. Theresidues were dissolved again in water. The pH was adjusted to 4 with 2mol/L hydrochloric acid, and it was extracted with chloroform and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residues were purified by silica gel columnchromatography (10% to 20% methanol/chloroform) to obtain the titlecompound as colorless amorphous.

¹H-NMR (CD₃OD) δ: 7.92-7.87 (2H, m), 7.50 (1H, d, J=7.9 Hz), 7.30-7.09(11H, m), 7.03 (1H, d, J=7.5 Hz), 6.90 (1H, ddd, J=8.2, 7.3, 0.7 Hz),5.11 (1H, dd, J=8.2, 4.9 Hz), 4.99 (2H, s), 3.19-2.82 (12H, m),2.41-2.14 (4H, m), 1.78-1.46 (4H, m).

ESI-MS Found: m/z 592 (M+H)⁺

Compounds of Examples 2 to 49, which have been produced by using thecorresponding compound of Reference example according to the same methodas Example 1, are shown in Table 22 to Table 32.

TABLE 22 ESI-MS Example Structural formula ¹H-NMR (M + H) ⁺ 2

(CD₃OD) δ: 7.78- 7.75 (2H, m), 7.52- 7.49 (1H, m), 7.26- 7.10 (11H, m),6.99 (1H, d, J = 7.5 Hz), 6.88 (1H, ddd, J = 8.2, 7.5, 0.9 Hz), 4.97(1H, d, J = 11.5 Hz), 4.92 (1H, d, J = 11.5 Hz), 4.67- 4.59 (1H, m),3.06-2.73 (13H, m), 2.23 (2H, t, J = 606 6.9 Hz), 2.13-2.05 (1H, m),1.93- 1.50 (6H, m). 3

(CD₃OD) δ: 7.78- 7.73 (2H, m), 7.32- 7.28 (3H, m), 7.23- 7.06 (9H, m),7.00 (1H, d, J = 7.5 Hz), 6.86 (1H, ddd, J = 8.2, 7.5, 0.9 Hz), 4.98(2H, s), 4.22 (1H, d, J = 6.6 Hz), 3.13-2.63 (12H, m), 2.16 (2H, t, J =7.1 Hz), 1.92- 1.40 (10H, m). 620 4

(DMSO-D₆) δ: 7.43 (1H, d, J = 8.1 Hz), 7.34 (1H, dd, J = 8.1, 1.6 Hz),7.29-7.07 (12H, m), 6.98 (1H, dd, J = 8.2, 1.2 Hz), 6.84 (1H, ddd, J =8.2, 7.5, 1.2 Hz), 5.00 (1H, d, J = 11.9 Hz), 4.95 (1H, d, J = 11.9 Hz),4.30- 4.21 (1H, m), 4.11-3.98 (2H, m), 608 3.05-2.57 (10H, m), 2.13 (2H,t, J = 7.1 Hz), 2.00- 1.80 (2H, m), 1.57- 1.36 (4H, m). 5

(DMSO-D₆) δ: 7.58 (2H, d, J = 8.6 Hz), 7.48 (1H, dd, J = 8.0, 1.8 Hz),1.29-1.01 (11H, m), 6.98 (1H, dd, J = 8.2, 1.2 Hz), 6.84 (1H, ddd, J =8.5, 7.4, 1.2 Hz), 4.98 (2H, s), 3.99-3.88 (1H, m), 3.10- 2.93 (2H, m),2.90 (4H, s), 2.83- 624 2.63 (4H, m), 2.58- 2.42 (2H, m), 2.28-2.08 (3H,m), 2.01-1.85 (1H, m), 1.58-1.35 (4H, m). 6

(DMSO-D₆) δ: 7.89 (1H, d, J = 8.1 Hz), 7.72 (1H, d, J = 8.1 Hz),7.30-7.03 (11H, m), 6.97 (1H, d, J = 8.1 Hz), 6.83 (1H, t, J = 7.3 Hz),4.97 (1H, d, J = 11.9 Hz), 4.92 (1H, d, J = 11.9 Hz), 4.01- 3.88 (1H,m), 2.89 (4H, s), 2.86- 607 2.56 (6H, m), 2.48-2.37 (2H, m), 2.11 (2H,t, J = 6.9 Hz), 1.99-1.81 (2H, m), 1.65- 1.31 (6H, m).

TABLE 23 7

(CD₃OD) δ: 7.52 (1H, dd, J = 7.7, 1.5Hz), 7.34-7.11 (12H, m), 7.08 (1H,dd, J = 7.5, 1.5 Hz), 6.96 (1H, dd, J = 6.3, 1.0 Hz), 6.85 (1H, ddd, J =8.2, 7.7, 1.0 Hz), 4.95 (2H, s), 4.81 (1H, dd, J = 8.3, 3.7 Hz), 4.48(1H, dd, J = 10.6, 3.7 Hz), 4.33 (1H, dd, J = 10.6, 8.3 Hz), 2.89-2.69(8H, m), 2.63-2.51 (1H, m), 2.50-2.38 (1H, m), 2.15 (2H, t, J = 6.7 Hz),1.50-1.40 (4H, m). 594 8

(DMSO-D₆) δ: 7.70 (1H, d, J = 8.1 Hz), 7.60 (1H, s), 7.46 (1H, d, J =8.1 Hz), 7.29-7.05 (11H, m), 6.96 (1H, dd, J = 8.0, 1.1 Hz), 6.83 (1H,ddd, J = 8.3, 7.3, 1.1 Hz), 4.99 (1H, d, J = 12.2 Hz), 4.94 (1H, d, J =12.2 Hz), 4.68 (1H, d, J = 15.0 Hz), 4.57 (1H, d, J = 15.0 Hz),3.95-3.78 (3H, m), 3.00- 2.42 (10H, m), 2.10 (2H, t, J = 7.1 Hz),1.54-1.36 (4H, m). 608 9

(DMSO-D₆) δ: 7.70 (1H, d, J = 8.8 Hz), 7.62-7.57 (2H, m), 7.21-7.08(13H, m), 4.02-3.92 (1H, m), 2.88-2.62 (12H, m), 2.46-2.39 (4H, m), 2.19(2H, t, J = 6.7 Hz), 1.99-1.89 (2H, m), 1.57-1.49 (6H, m). 604 10

(CD₃OD) δ: 7.68-7.65 (2H, m), 7.49 (1H, d, J = 8.4 Hz), 7.30- 7.01 (11H,m), 6.93-6.85 (2H, m), 4.84 (1H, d, J = 11.0 Hz), 4.79 (1H, d, J = 11.0Hz), 4.31-4.28 (1H, m), 2.96-2.63 (12H, m), 2.15 (2H, t, J = 6.4 Hz),1.98-1.80 (2H, m), 1.59- 1.46 (6H, m). 606 11

(CD₃OD) δ: 7.73-7.71 (2H, m), 7.54-7.51 (1H, m), 7.27-7.09 (11H, m),6.96-6.84 (2H, m), 4.93 (1H, d, J = 11.7 Hz), 4.90 (1H, d, J = 11.7 Hz),4.52-4.47 (1H, m), 2.98-2.69 (12H, m), 2.20 (2H, t, J = 6.7 Hz), 2.09-2.00 (1H, m), 1.91-1.82 (1H, m), 1.76-1.45 (6H, m). 606

TABLE 24 12

(CD₃OD) δ: 7.83-7.77 (2H, m), 7.62-7.50 (1H, m), 7.38-7.31 (5H, m), 7.22(1H, t, J = 7.9 Hz), 7.13 (1H, d, J = 6.0 Hz), 7.00 (1H, d, J = 8.2 Hz),6.89 (1H, t, J = 7.2 Hz), 4.99 (2H, s), 4.87-4.79 (1H, m), 3.15-2.77(8H, m), 2.25 (2H, t, J = 7.0 Hz), 2.17-2.08 (1H, m), 1.92-1.47 (7H, m).502 13

(CD₃OD) δ: 7.70-7.65 (2H, m), 7.53 (1H, d, J = 8.8 Hz), 7.44-7.39 (2H,m), 7.36-7.25 (2H, m), 7.23- 7.16 (1H, m), 7.11 (1H, dd, J = 7.3, 1.5Hz), 6.95 (1H, d, J = 8.1 Hz), 6.88 (1H, ddd, J = 7.8, 7.3, 0.6 Hz),5.06 (1H, d, J = 12.0 Hz), 5.01 (1H, d, J = 12.0 Hz), 4.42-4.33 (1H, m),2.98-2.71 (8H, m), 2.20 (2H, t, J = 6.7 Hz) , 2.09-2.00 (1H, m),1.94-1.86 (1H, m), 1.74-1.53 (6H, m). 536 14

(CDCl₃) δ: 7.82-7.70 (3H, m), 7.47-7.21 (7H, m), 7.20-7.09 (2H, m),6.97-6.83 (4H, m), 5.05 (2H, s), 4.89 2H, s), 4.08-3.99 (1H, m),2.97-2.84 (1H, m), 2.83-2.64 (5H, m), 2.42 (2H, t, J = 6.8 Hz), 2.22(2H, t, J = 7.0 Hz), 2.03- 1.82 (2H, m), 1.66-1.32 (6H, m). 608 15

(CD₃OD) δ: 7.74-7.67 (2H, m), 7.55-7.48 (1H, m), 7.35-7.06 (11H, m),6.93 (1H, d, J = 7.5 Hz), 6.86 (1H, ddd, J = 8.2, 7.5, 0.9 Hz), 4.91(1H, d, J = 11.5 Hz), 4.86 (1H, d, J = 11.5 Hz), 4.43-4.33 (1H, m), 4.14(2H, s), 3.00-2.63 (8H, m), 2.21 (2H, t, J = 7.0 Hz), 2.08-1.95 (1H, m),1.93-1.80 (1H, m), 1.73-1.44 (6H, m). 624 16

(CD₃OD) δ: 7.73-7.68 (2H, m), 7.52 (1H, d, J = 8.6 Hz), 7.43 (2H, d, J =8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.30-7.14 (3H, m), 7.10 (1H, dd, J =7.5, 1.6 Hz), 7.01-6.94 (3H, m), 6.94-6.83 (2H, m), 5.07 (2H, s), 4.98(1H, d, J = 11.5 Hz), 4.93 (1H, d, J = 11.5 Hz), 4.45-4.35 (1H, m),3.02-2.63 (8H, m), 2.19 (2H, t, J = 6.6 Hz) , 2.10-1.79 (2H, m),1.75-1.41 (6H, m). 608

TABLE 25 17

(CD₃OD) δ: 7.74-7.66 (2H, m), 7.51 (1H, d, J = 8.6 Hz), 7.35- 7.06 (11H,m), 6.95 (1H, d, J = 7.5 Hz), 6.86 (1H, ddd, J = 8.2, 7.5, 0.9 Hz),4.95-4.86 (2H, m), 4.48-4.40 (1H, m), 4.14 (2H, s), 3.03-2.60 (8H, m),2.21 (2H, t, J = 6.5 Hz), 2.10-1.81 (2H, m), 1.81-1.42 (6H, m). 624 18

(CD₃OD) δ: 7.70-7. 68 (2H, m), 7.50 (1H, d, J = 8.4 Hz), 7.36 (2H, d, J= 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.21-7.15 (1H, m), 7.10-7.01 (3H,m), 6.96 (1H, d, J = 8.3 Hz), 6.86 (1H, ddd, J = 8.4, 7.5, 1.1 Hz),6.63-6.54 (3H, m), 4.95 (1H, d, J = 11.4 Hz), 4.90 (1H, d, J = 11.4 Hz),4.38- 4.32 (1H, m), 4.32 (2H, s), 2.94- 2.66 (8H, m), 2.19 (2H, t, J =6.6 Hz), 2.04-1.99 (1H, m), 1.88- 1.85 (1H, m), 1.66-1.52 (6H, m). 60719

(CD₃OD) δ: 7.71-7.66 (2H, m), 7.52 (1H, d, J = 8.6 Hz), 7.43 (2H, d, J =8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.21-7.14 (1H, m), 7.11 (1H, dd, J =7.3, 1.6 Hz), 6.93 (1H, d, J = 7.8 Hz), 6.90- 6.83 (1H, m), 4.97 (1H, d,J = 11.9 Hz), 4.92 (1H, d, J = 11.9 Hz), 4.40-4.32 (1H, m), 3.48 (1H,s), 2.99-2.66 (8H, m), 2.22 (2H, t, J = 6.4 Hz), 2.11-1.85 (2H, m),1.76-1.46 (6H, m). 526 20

(CD₃OD) δ: 7.62-7.57 (2H, m), 7.42 (1H, d, J = 8.8 Hz), 7.22 (2H, d, J =8.3 Hz), 7.15 (2H, d, J = 8.3 Hz), 7.12-7.05 (1H, m), 7.01 (1H, dd, J =7.5, 1.8 Hz), 6.85 (1H, dd, J = 8.4, 0.7 Hz) , 6.77 (1H, ddd, J = 8.4,7.5, 1.0 Hz), 4.85 (1H, d, J = 11.6 Hz), 4.80 (1H, d, J = 11.6 Hz),4.31- 4.21 (1H, m), 2.90-2.55 (9H, m), 2.13 (2H, t, J = 6.3 Hz), 2.01-1.74 (2H, m), 1.66-1.34 (6H, m), 1.16 (6H, d, J = 7.0 Hz). 568

TABLE 26 21

(CD₃OD) δ: 7.75-7.70 (2H, m), 7.51 (1H, d, J = 8.8 Hz), 7.30 (2H, d, J =8.3 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.22-7.15 (1H, m), 7.11 (1H, dd, J =7.6, 1.6 Hz), 6.95 (1H, d, J = 8.2 Hz), 6.88 (1H, ddd, J = 8.2, 7.6, 0.9Hz), 4.96 (1H, d, J = 12.0 Hz), 4.91 (1H, d, J = 12.0 Hz), 4.50-4.47(1H, m), 3.08-2.62 (8H, m), 2.24 (2H, t, J = 6.5 Hz), 2.14-1.83 (2H, m),1.80-1.36 (7H, m), 0.94- 0. 66 (4H, m). 566 22

(CD₃OD) δ: 7.72-7.68 (2H, m), 7.52 (1H, d, J = 9.0 Hz), 7.32 (2H, d, J =8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.22-7.15 (1H, m), 7.10 (1H, dd, J =7.5, 1.5 Hz), 6.95 (1H, d, J = 8.5 Hz), 6.87 (1H, ddd, J = 8.5, 7.5, 0.9Hz), 4.95 (1H, d, J = 11.5 Hz), 4.90 (1H, d, J = 11.5 Hz), 4.46-4.31(1H, m), 3.03-2.48 (9H, m), 2.23- 2.20 (2H, m), 2.11-1.29 (18H, m). 60823

(CD₃OD) δ: 7.77-7.70 (2H, m), 7.53 (1H, d, J = 7.6 Hz), 7.32 (2H, d, J =8.2 Hz), 7.25 (2H, d, J = 8.2 Hz), 7.22-7.17 (1H, m), 7.10 (1H, dd, J =7.5, 1.6 Hz), 6.98 (1H, d, J = 7.5 Hz), 6.87 (1H, ddd, J = 8.4, 7.5, 0.9Hz), 6.35 (1H, d, J = 15.9 Hz), 6.19 (1H, dd, J = 15.9, 6.8 Hz), 4.91(2H, s), 4.55-4.44 (1H, m), 2.95 (2H, t, J = 7.5 Hz), 2.87-2.62 (6H, m),2.20 (2H, t, J = 7.8 Hz), 2.17-1.95 (2H, m), 1.94-1.09 (17H, m). 610 24

(CD₃OD) δ: 7.72-7.67 (2H, m), 7.51 (1H, d, J = 8.5 Hz), 7.23 (2H, d, J =7.9 Hz), 7.18-7.08 (4H, m), 6.98 (1H, d, J = 8.2 Hz), 6.86 (1H, dd, J =7.9, 7.9 Hz), 4.93 (1H, d, J = 11.2 Hz), 4.88 (1H, d, J = 11.2 Hz),4.44- 4.32 (1H, m), 3.02-2.53 (10H, m), 2.19 (2H, t, J = 6.6 Hz), 2.10-1.84 (2H, m), 1.84-1.41 (13H, m), 1.35-1.12 (4H, m), 1.05-0.85 (2H, m).612

TABLE 27 25

(CD₃OD) δ: 7.72-7.69 (2H, m), 7.52 (1H, d, J = 8.2 Hz), 7.36- 7.06 (7H,m), 6.85-6.81 (2H, m), 6.36 (1H, d, J = 15.9 Hz), 6.18 (1H, dd, J =15.9, 7.0 Hz), 4.34- 4.32 (1H, m), 3.74-3.60 (2H, m), 2.92-2.78 (8H, m),2.20-2.10 (5H, m), 1.88-1.62 (11H, m), 1.23-1.12 (4H, m). 610 26

(CD₃OD) δ: 7.76-7.64 (2H, m), 7.51 (1H, d, J = 7.9 Hz), 7.29- 7.01 (7H,m), 6.86-6.76 (2H, m), 4.39-4.27 (1H, m), 3.73-3.53 (2H, m), 2.99-2.67(8H, m), 2.62 (2H, t, J = 7.9 Hz), 2.34-1.92 (4H, m), 1.90-1.42 (12H,m), 1.32-1.12 (2H, m), 1.09-0.87 (4H, m). 612 27

(CD₃OD) δ: 7.69 (1H, d, J = 1.6 Hz), 7.62 (1H, dd, J = 8.0, 1.6 Hz),7.40 (1H, d, J = 8.0 Hz), 7.29-7.04 (7H, m), 6.87-6.79 (2H, m),4.29-4.25 (1H, m), 3.76 (1H, dd, J = 9.0, 6.6 Hz), 3.65 (1H, dd, J =9.0, 7.3 Hz), 2.92-2.68 (8H, m), 2.62-2.56 (2H, m), 2.32- 2.22 (2H, m),2.19-1.93 (2H, m), 1.85-1.26 (18H, m). 612 28

(CD₃OD) δ: 7.70-7.69 (2H, m), 7.51 (1H, d, J = 8.8 Hz), 7.18 (1H, ddd, J= 9.3, 8.1, 1.8 Hz), 7.09 (1H, dd, J = 7.5, 1.8 Hz), 7.05-6.93 (4H, m),6.85 (1H, ddd, J = 8.2, 7.5, 0.9 Hz), 4.91-4.78 (2H, m), 4.44-4.35 (1H,m), 3.01- 2.63 (12H, m), 2.17 (2H, t, J = 6.6 Hz), 2.09-1.82 (2H, m),1.80- 1.75 (2H, m), 1.74-1.43 (8H, m). 556 29

(DMSO-D₆) δ: 7.62-7.56 (2H, m), 7.50 (1H, d, J = 8.0 Hz), 7.18- 7.10(2H, m), 7.10-6.98 (4H, m), 6.83 (1H, ddd, J = 8.2, 7.3, 0.9 Hz), 4.96(1H, d, J = 12.0 Hz), 4.92 (1H, d, J = 12.0 Hz), 3.89 (1H, dd, J = 8.6,5.3 Hz), 2.85- 2.55 (10H, m), 2.39 (2H, t, J = 6.4 Hz), 2.04 (2H, t, J =7.2 Hz), 1.94-1.64 (6H, m), 1.59-1.29 (6H, m). 556

TABLE 28 30

(CD₃OD) δ: 7.74-7.68 (2H, m), 7.52 (1H, d, J = 8.6 Hz), 7.21- 7.14 (1H,m), 7.08 (1H, dd, J = 7.5, 1.6 Hz), 6.94 (1H, dd, J = 7.5, 1.0 Hz), 6.85(1H, ddd, J = 8.4, 7.5, 1.1 Hz), 6.81-6.77 (3H, m), 4.88-4.78 (2H, m),4.49 4.37 (1H, m), 4.21 (4H, s), 3.04-2.66 (8H, m), 2.21 (2H, t, J = 6.6Hz), 2.14-2.01 (1H, m), 1.99-1.85 (1H, m), 1.78-1.55 (6H, m). 560 31

(CD₃OD) δ: 7.72-7.69 (2H, m), 7.51 (1H, d, J = 8.8 Hz), 7.22- 7.15 (1H,m), 7.09 (1H, dd, J = 7.5, 1.6 Hz), 7.05-6.95 (3H, m), 6.85 (1H, ddd, J= 8.4, 7.5, 1.0 Hz), 6.69 (1H, d, J = 7.5 Hz), 4.83 (2H, s), 4.46-4.35(1H, m), 4.17-4.11 (2H, m), 2.97-2.65 (10H, m), 2.19 (2H, t, J = 6.6Hz), 2.10-1.82 (4H, m), 1.77- 1.39 (6H, m). 558 32

(CD₃OD) δ: 7.77-7.68 (2H, m), 7.52 (1H, d, J = 8.8 Hz), 7.19 (1H, ddd, J= 8.3, 7.5, 1.6 Hz) , 7.10 (1H, dd, J = 7.5, 1.6 Hz) , 7.05-6.93 (4H,m), 6.86 (1H, ddd, J = 8.4, 7.5, 0.9 Hz), 4.84 (2H, s), 4.49-4.40 (1H,m), 3.04-2.64 (12H, m), 2.20 (2H, t, J = 6.6 Hz), 2.11-1.95 (3H, m),1.95-1.81 (1H, m), 1.76-1.40 (6H, m). 574 33

(CD₃OD) δ: 7.72-7.67 (2H, m), 7.51 (1H, d, J = 7.5 Hz), 7.18 (1H, ddd, J= 8.0, 7.5, 1.6 Hz), 7.09 (1H, dd, J = 7.5, 1.6 Hz), 6.95 (1H, d, J =7.5 Hz), 6.86 (1H, ddd, J = 8.4, 7.5, 0.9 Hz), 6.83-6.75 (3H, m), 5.94(2H, s), 4.88-4.80 (2H, m), 4.47-4.38 (1H, m), 3.01-2.67 (8H, m), 2.21(2H, t, J = 6.6 Hz), 2.14-2.01 (1H, m), 1.99-1.87 (1H, m), 1.79-1.46(6H, m). 546

TABLE 29 34

(CD₃OD) δ: 7.78-7.69 (2H, m), 7.53 (1H, d, J = 8.6 Hz), 7.19 (1H, ddd, J= 8.2, 7.5, 1.7 Hz), 7.09 (1H, dd, J = 7.5, 1.7 Hz), 6.99 (1H, dd, J =8.2, 1.0 Hz), 6.87 (1H, ddd, J = 8.4, 7.5, 1.0 Hz), 6.67 (1H, s), 5.05(1H, d, J = 11.7 Hz), 5.00 (1H, d, J = 11.7 Hz), 4.55-4.45 (1H, m),3.00-2.86 (3H, m), 2.85-2.72 (5H, m), 2.69 (2H, t, J = 5.6 Hz), 2.54(2H, t, J = 5.6 Hz), 2.21 (2H, t, J = 6.8 Hz), 2.17-2.05 (1H, m),2.01-1.87 (1H, m), 1.87-1.44 (10H, m). 562 35

(CD₃OD) δ: 7.70-7.60 (2H, m), 7.48 (1H, d, J = 8.1 Hz), 7.17 (1H, ddd, J= 8.1, 7.3, 1.7 Hz), 7.11-7.07 (1H, m), 7.06-6.97 (4H, m), 6.91-6.80(2H, m), 4.40-4.26 (1H, m), 3.91-3.72 (2H, m), 3.03- 2.62 (11H, m),2.61-2.46 (1H, m), 2.22 (2H, t, J = 6.5 Hz), 2.18- 1.86 (4H, m),1.83-1.40 (7H, m). 556 36

(CD₃OD) δ: 7.75-7.71 (2H, m), 7.51-7.47 (1H, m), 7.26-6.95 (11H, m),6.90-6.84 (1H, m), 5.44-5.39 (1H, m), 4.50-4.41 (1H, m), 2.96-2.61 (14H,m), 2.22-1.42 (14H, m). 646 37

(CD₃OD) δ: 7.83-7.77 (2H, m), 7.53 (1H, d, J = 8.8 Hz), 7.27- 7.09 (11H,m), 7.00 (1H, d, J = 7.7 Hz), 6.92-6.86 (1H, m), 4.95 (2H, s), 4.85-4.80(1H, m), 3.19- 2.73 (14H, m), 2.13-2.09 (1H, m), 1.90-1.55 (7H, m). 63038

(CD₃OD) δ: 7.79 (1H, dd, J = 8.2, 1.6 Hz), 7.74 (1H, d, J = 1.6 Hz),7.64 (1H, d, J = 8.2 Hz), 7.37-7.26 (5H, m), 7.22 (1H, ddd, J = 8.4,8.2, 1.6 Hz), 7.12 (1H, dd, J = 7.5, 1.6 Hz), 7.04 (1H, dd, J = 8.2, 0.8Hz), 6.90 (1H, ddd, J = 8.4, 7.5, 0.8 Hz), 4.88 (1H, d, J = 16.0 Hz),4.81 (1H, d, J = 16.0 Hz), 4.62-4.50 (1H, br m), 3.04-2.79 (6H, m),2.79- 2.64 (2H, m), 2.25 (2H, t, J = 6.6 Hz), 2.21-2.13 (1H, m), 2.02-1.88 (1H, m), 1.88-1.52 (6H, m). 526

TABLE 30 39

(CD₃OD) δ: 8.50 (1H, s), 7.86 (1H, s), 7.29-7.06 (11H, m), 6.98-6.82(2H, m), 4.90 (1H, d, J = 12.0 Hz), 4.85 (1H, d, J = 12.0 Hz), 4.21-4.08(1H, m), 2.88 (4H, s), 2.86-2.73 (6H, m), 2.58-2.32 (2H, m), 2.24-1.87(4H, m), 1.73-1.24 (6H, m). 607 40

(CD₃OD) δ: 7.84-7.77 (2H, m), 7.53 (1H, d, J = 8.5 Hz), 7.42 (2H, d, J =8.5 Hz), 7.31-7.20 (3H, m), 7.16-7.11 (1H, m), 7.02 (1H, d, J = 8.3 Hz),6.90 (1H, ddd, J = 8.5, 7.5, 1.1 Hz), 4.97 (2H, s), 4.87- 4.75 (1H, m),3.15-2.74 (8H, m), 2.25 (2H, t, J = 7.0 Hz), 2.15- 2.07 (1H, m),1.84-1.49 (7H, m), 1.32 (9H, s). 558 41

(CD₃OD) δ: 7.71-7.65 (2H, m), 7.52-7.47 (1H, m), 7.41-7.33 (2H, m),7.31-7.24 (1H, m), 7.23-7.08 (3H, m), 7.01-6.95 (1H, m), 6.90- 6.83 (1H,m), 4.98 (1H, d, J = 11.4 Hz), 4.91 (1H, d, J = 11.4 Hz), 4.43-4.31 (1H,m), 3.02-2.64 (8H, m), 2.18 (2H, t, J = 6.5 Hz), 2.09-1.97 (1H, m),1.94-1.81 (1H, m), 1.75-1.41 (6H, m), 1.30 (9H, s). 558 42

(CD₃OD) δ: 7.76-7.73 (2H, m), 7.53-7.50 (1H, m), 7.23-7.17 (3H, m),7.11-6.97 (4H, m), 6.89-6.84 (1H, m), 4.93 (1H, d, J = 11.2 Hz), 4.89(1H, d, J = 11.2 Hz), 4.57-4.52 (1H, m), 2.99-2.94 (3H, m), 2.82-2.72(5H, m), 2.21 (2H, t, J = 6.8 Hz), 2.04-1.85 (3H, m), 1.73-1.48 (6H, m),0.99-0.93 (2H, m), 0.69-0.63 (2H, m). 542 43

(DMSO-D₆) δ: 7.58-7.56 (2H, m), 7.21-7.14 (7H, m), 6.97 (1H, d, J = 8.1Hz), 6.82 (1H, t, J = 7.4 Hz), 5.06 (1H, s), 4.94 (1H, d, J = 12.0 Hz),4.88 (1H, d, J = 12.0 Hz), 3.94-3.88 (1H, m), 2.90-2.85 (2H, m),2.71-2.63 (4H, m), 2.43- 2.42 (3H, m), 2.11-2.09 (2H, m), 1.98-1.84 (2H,m), 1.49-1.38 (5H, m), 1.18 (6H, d, J = 6.8 Hz). 544

TABLE 31 44

(CD₃OD) δ: 7.76 (2H, d, J = 6.1 Hz), 7.63 (1H, t, J = 9.3 Hz), 7.34-7.27(2H, m), 7.20 (1H, d, J = 8.4 Hz), 7.14-6.96 (3H, m), 6.80-6.66 (2H, m),5.32-5.17 (1H, m), 4.55-4.42 (1H, m), 3.03-2.75 (8H, m), 2.32-2.13 (3H,m), 2.08- 1.94 (1H, m), 1.90-1.56 (6H, m), 1.48, 1.45 (3H, each d, J =6.4 Hz), 1.29, 1.27 (9H, each s). 572 45

(CD₃OD) δ: 7.78-7.72 (2H, m), 7.68-7.59 (1H, m), 7.34-7.27 (2H, m), 7.20(1H, d, J = 8.4 Hz), 7.14-6.96 (3H, m), 6.80-6.66 (2H, m), 5.32-5.17(1H, m), 4.48-4.38 (1H, m), 3.03-2.75 (8H, m), 2.32- 2.13 (3H, m),2.08-1.94 (1H, m), 1.90-1.56 (6H, m), 1.47, 1.44 (3H, each d, J = 6.4Hz), 1.28, 1.27 (9H, each s). 572 46

(CD₃OD) δ: 7.75-7.66 (2H, m), 7.51 (1H, d, J = 8.6 Hz), 7.24-7.13 (3H,m), 7.12-7.04 (2H, m), 6.98 (1H, d, J = 7.7 Hz), 6.86 (1H, ddd, J = 8.2,7.4, 0.9 Hz), 4.90 (2H, s), 4.54-4.33 (1H, m), 3.02- 2.63 (12H, m), 2.18(2H, t, J = 6.8 Hz), 2.12-1.96 (3H, m), 1.95- 1.79 (1H, m), 1.78-1.39(6H, m). 542 47

(CD₃OD) δ: 7.95-7.82 (2H, m), 7.47 (1H, d, J = 7.9 Hz), 7.30-7.19 (1H,m), 7.18-6.98 (5H, m), 6.89 (1H, ddd, J = 8.2, 7.3, 0.9 Hz), 5.10-5.02(1H, m), 4.94 (2H, s), 3.17-2.79 (7H, m), 2.78-2.66 (4H, m), 2.39-2.23(2H, m), 2.19 (2H, t, J = 6.8 Hz), 1.83-1.41 (9H, m). 594 48

(DMSO-D₆) δ: 7.42 (1H, d, J = 8.0 Hz), 7.33 (1H, dd, J = 8.0, 1.7 Hz),7.21 (1H, d, J = 1.7 Hz), 7.16-6.96 (6H, m), 6.83 (1H, ddd, J = 8.6,7.5, 1.3 Hz), 4.94 (1H, d, J = 11.5 Hz), 4.89 (1H, d, J = 11.5 Hz),4.29-4.20 (1H, m), 4.11- 3.96 (2H, m), 3.02-2.58 (11H, m), 2.15-2.05(2H, m), 1.98-1.82 (2H, m), 1.78-1.65 (4H, m), 1.55-1.35 (3H, m). 558

49

(DMSO-D₆) δ: 7.46-7.20 (10H, m), 7.16-7.05 (2H, m), 7.01-6.94 (3H, m),6.83 (1H, ddd, J = 8.5, 7.3, 1.1 Hz), 5.10 (2H, S), 4.96 (1H, d, J =11.9 Hz), 4.91 (1H, d, J = 11.9 Hz), 4.29-4.20 (1H, m), 4.09-3.96 (2H,m), 2.85-2.55 (4H, m), 2.53- 2.40 (2H, m), 2.13 (2H, t, J = 7.1 Hz),1.99-1.80 (2H, m), 1.58-1.35 (4H, m). 610

Compounds of Examples 50 to 69, which have been produced by using thecorresponding optically active compound of Reference Example accordingto the same method as Example 1, are shown in Table 33 to Table 37.

TABLE 33 Optical rotation [α]_(D) ESI-MS Optical Example Structuralformula ¹H-NMR (M + H)⁺ purity 50

(CD₃OD) δ: 7.76-7.76 (2H, m), 7.54-7.51 (1H, m), 7.26-7.10 (11H, m),6.99 (1H, d, J = 7.7 Hz), 6.88 (1H, dd, J = 7.6, 0.9 Hz), 4.96 (1H, d, J= 11.6 Hz), 4.92 (1H, d, J = 11.6 Hz), 4.65-4.63 (1H, m), 3.07- 2.73(12H, m), 2.23 (2H, t, J = 6.9 Hz), 2.14- 2.08 (1H, m), 1.90-1.49 (7H,m). 606 +74.0 (c = 0.66, CHCl₃) 99.84% ee 51

(CD₃OD) δ: 7.75-7.73 (2H, m), 7.52-7.50 (1H, m), 7.25-7.09 (11H, m),6.98 (1H, d, J = 7.5 Hz), 6.87 (1H, td, J = 7.4, 1.0 Hz), 4.95 (1H, d, J= 11.4 Hz), 4.91 (1H, d, J = 11.4 Hz), 4.57-4.52 (1H, m), 3.00- 2.72(12H, m), 2.22 (2H, t, J = 6.8 Hz), 2.09- 2.06 (1H, m), 1.90-1.88 (1H,m), 1.75-1.52 (6H, m). 606 −78.0 (c = 0.24, CHCl₃) 98.76% ee 52

(CD₃OD) δ: 7.96-7.85 (2H, m), 7.50 (1H, d, J = 8.1 Hz), 7.34-7.08 (11H,m), 7.04 (1H, d, J = 8.3 Hz), 6.90 (1H, ddd, J = 8.3, 7.5, 0.9 Hz), 5.10(1H, dd, J = 8.3, 4.9 Hz), 4.99 (2H, s), 3.23-2.80 (12H, m), 2.44-2.13(4H, m), 1.83- 1.43 (4H, m). 592 +26.2 (c = 0.49, MeOH) 99.44% ee

TABLE 34 53

(CD₃OD) δ: 7.92-7.83 (2H, m), 7.46 (1H, d, J = 7.9 Hz), 7.32- 7.08 (11H,m), 7.02 (1H, d, J = 8.1 Hz), 6.89 (1H, ddd, J = 8.3, 7.5, 0.9 Hz), 5.05(1H, dd, J = 8.3, 5.0 Hz), 4.98 (2H, s), 3.15-2.78 (12H, m), 2.42- 2.09(4H, m), 1.78-1.43 (4H, m). 592 −34.7 (c = 0.48, MeOH) 99.60% ee 54

(DMSO-D₆) δ: 7.41 (1H, d, J = 8.1 Hz), 7.34-7.09 (13H, m), 6.98 (1H, d,J = 8.1 Hz), 6.84 (1H, t, J = 7.4 Hz), 4.97 (1H, d, J = 11.7 Hz), 4.91(1H, d, J = 11.7 Hz), 4.30-4.26 (1H, m), 4.12-3.97 (2H, m), 3.34-3.30(1H, m), 2.86 (4H, s), 2.82- 2.54 (3H, m), 2.44-2.40 (2H, m), 2.11 (2H,t, J = 6.5 Hz), 2.02-1.73 (2H, m), 1.49-1.32 (4H, m). 608 +67.0 (c =0.27, MeOH) 99.99% ee 55

(DMSO-D₆) δ: 7.41 (1H, d, J = 8.1 Hz), 7.34-7.09 (13H, m), 6.98 (1H, d,J = 8.1 Hz), 6.84 (1H, t, J = 7.4 Hz), 4.97 (1H, d, J = 11.7 Hz), 4.91(1H, d, J = 11.7 Hz), 4 .30-4.26 (1H, m), 4.12-3.97 (2H, m), 3.33-3.31(1H, m), 2.86 (4H, S), 2.81- 2.54 (3H, m), 2.44-2.40 (2H, m), 2.12 (2H,t, J = 6.4 Hz), 1.92-1.78 (2H, m), 1.50-1.35 (4H, m). 608 −63.2 (c =0.25, MeOH) 99.99% ee 56

(CD₃OD) δ: 7.82-7.79 (2H, m), 7.57 (1H, d, J = 8.2 Hz), 7.21 (1H, t, J =7.7 Hz), 7.11 (1H, d, J = 7.1 Hz), 6.98 (1H, d, J = 8.2 Hz), 6.90-6.82(4H, m), 4.88-4.76 (3H, m), 4.22 (4H, s), 3.14-2.77 (8H, m), 2.25 (2H,t, J = 6.9 Hz), 2.16-2.09 (1H, m), 1.97-1.50 (7H, m). 560 +48.2 (c =0.25, MeOH) 57

(CD₃OD) δ: 7.85-7.83 (2H, m), 7.56 (1H, d, J = 8.8 Hz), 7.23 (1H, ddd, J= 9.9, 7.5, 1.7 Hz), 7.12 (1H, dd, J = 7.3, 1.3 Hz), 7.00 (1H, d, J =8.1 Hz), 6.91-6.83 (4H, m), 4.92-4.87 (3H, m), 4.23 (4H, s), 3.22- 2.80(8H, m), 2.27 (2H, t, J = 7.1 Hz), 2.19-2.12 (1H, m), 1. 97-1.47 (7H,m). 560 −52.1 (c = 0.24, MeOH) 99.99% ee

TABLE 35 58

(CD₃OD) δ: 7.74-7.66 (2H, m), 7.50 (1H, d, J = 8.8 Hz), 7.20 (1H, t, J =7.6 Hz), 7.11-6.97 (5H, m), 6.87 (1H, t, J = 7.6 Hz), 4.95-4.85 (2H, m),4.40 (1H, s), 2.98-2.65 (12H, m), 2.17 (2H, t, J = 6.4 Hz), 2.05-1.43(12H, m). 556 +80.1 (c = 0.29, MeOH) 99.32% ee 59

(CD₃OD) δ: 7.72-7.65 (2H, m), 7.50 (1H, d, J = 8.8 Hz), 7.20 (1H, ddd, J= 8.8, 7.3, 1.2 Hz), 7.11- 6.98 (5H, m), 6.87 (1H, ddd, J = 8.4, 7.3,0.9 Hz), 4.96-4.82 (2H, m), 4.37 (1H, t, J = 7.7 Hz), 2.98- 2.62 (12H,m), 2.17 (2H, t, J = 6.5 Hz), 2.05-1.92 (1H, m), 1.90-1.42 (11H, m). 556−81.8 (c = 0.36, MeOH) 99.88% ee 60

(DMSO-D₆) δ: 7.58-7.50 (3H, m), 7.39 (1H, s), 7.33 (1H, d, J = 7.9 Hz),7.27 (1H, t, J = 7.4 Hz), 7.19-7.08 (3H, m), 6.99 (1H, d, J = 8.1 Hz),6.84 (1H, t, J = 7.4 Hz), 4.99 (1H, d, J = 11.6 Hz), 4.91 (1H, d, J =11.6 Hz), 3.94-3.91 (1H, m), 3.33-3.31 (1H, m), 2.83-2.76 (1H, m), 2.68-2.56 (4H, m), 2.44-2.40 (2H, m), 2.10 (2H, t, J = 6.1 Hz), 1.95-1.84(2H, m), 1.50-1.31 (6H, m), 1.26 (9H, s). 558 +86.0 (c = 0.27, MeOH)99.64% ee 61

(DMSO-D₆) δ: 7.59-7.50 (3H, m), 7.39-7.24 (3H, m), 7.19-7.08 (3H, m),6.99 (1H, d, J = 8.1 Hz), 6.84 (1H, t, J = 7.5 Hz), 4.99 (1H, d, J =11.8 Hz), 4.91 (1H, d, J = 11.8 Hz), 3.93- 3.90 (1H, m), 3.33-3.31 (1H,m), 2.80-2.76 (1H, m), 2.67-2.55 (4H, m), 2.44- 2.40 (2H, m), 2.10 (2H,t, J = 7.0 Hz), 1.94-1.84 (2H, m), 1.47-1.32 (6H, m), 1.26 (9H, s). 558−78.0 (c = 0.25, MeOH) 99.99% ee

TABLE 36 62

(CD₃OD) δ: 7.76-7.69 (2H, m), 7.56-7.49 (1H, m), 7.25-7.14 (3H, m),7.13-7.01 (3H, m), 6.97 (1H, d, J = 8.2 Hz), 6.86 (1H, ddd, J = 8.1,7.3, 0.7 Hz), 4.92 (1H, d, J = 11.2 Hz), 4.87 (1H, d, J = 11.2 Hz), 4.45(1H, t, J = 7.3 Hz), 3.03-2.83 (3H, m), 2.83-2.63 (5H, m), 2.20 (2H, t,J = 6.6 Hz), 2.10-1.96 (1H, m), 1.95-1.81 (2H, m), 1.76-1.42 (6H, m),1.01-0.91 (2H, m), 0.70-0.62 (2H, m). 542 +86.2 (c = 0.19, MeOH) 99.42%ee 63

(CD₃OD) δ: 7.68-7.62 (2H, m), 7.47-7.41 (1H, m), 7.17-7.05 (3H, m),7.04-6.92 (3H, m), 6.88 (1H, d, J = 8.2 Hz), 6.77 (1H, ddd, J = 8.1,7.3, 0.7 Hz), 4.83 (1H, d, J = 11.2 Hz), 4.79 (1H, d, J = 11.2 Hz), 4.41(1H, t, J = 7.3 Hz), 3.02-2.77 (3H, m), 2.77-2.54 (5H, m), 2.11 (2H, t,J = 6.6 Hz), 2.02-1.88 (1H, m), 1.88-1.72 (2H, m), 1.69-1.32 (6H, m),0.93-0.81 (2H, m), 0.62-0.53 (2H, m). 542 −78.7 (c = 0.19, MeOH) 99.82%ee 64

(CD₃OD) δ: 7.91-7.89 (2H, m), 7.68-7.65 (1H, m), 7.32 (2H, d, J = 8.4Hz), 7.13-7.02 (4H, m), 6.82-6.73 (2H, m), 5.31 (1H, q, J = 6.2 Hz),5.06-5.00 (1H, m), 3.34-2.87 (8H, m), 2.37 (2H, t, J = 7.0 Hz),2.10-1.64 (7H, m), 1.51 (3H, d, J = 6.2 Hz), 1.29 (9H, s). 572 — 96.22%ee 65

(CD₃OD) δ: 7.79-7.76 (2H, m), 7.65 (1H, d, J = 8.1 Hz), 7.33 (2H, d, J =8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.08-7.00 (2H, m), 6.80-6.74 (2H, m),5.28 (1H, q, J = 6.4 Hz), 4.57-4.52 (1H, m), 3.07- 2.76 (8H, m), 2.28(2H, t, J = 6.8 Hz), 2.22-2.15 (1H, m), 2.02-1.98 (1H, m), 1.87-1.59(6H, m), 1.47 (3H, d, J = 6.4 Hz), 1.28 (9H, s). 572 — 99.67% ee

TABLE 37 66

(CD₃OD) δ: 7.74-7.68 (2H, m), 7.52 (1H, d, J = 8.8 Hz), 7.22-7.14 (3H,m), 7.09-7.07 (2H, m), 6.97 (1H, d, J = 8.2 Hz), 6.85 (1H, ddd, J = 8.4,7.5, 1.1 Hz), 4.94-4.86 (2H, m), 4.50-4.40 (1H, m), 3.00- 2.65 (12H, m),2.17 (2H, t, J = 6.7 Hz), 2.11-1.98 (3H, m), 1.93-1.80 (1H, m),1.74-1.40 (6H, m). 542 +79.4 (c = 0.30, MeOH) 99.32% ee 67

(CD₃OD) δ: 7.74-7.69 (2H, m), 7.51 (1H, d, J = 8.6 Hz), 7.22-7.15 (3H,m), 7.10-7.08 (2H, m), 6.98 (1H, d, J = 7.5 Hz), 6.86 (1H, ddd, J = 8.4,7.3, 0.9 Hz), 4.95-4.85 (2H, m), 4.47 (1H, t, J = 7.6 Hz), 2.97-2.71(12H, m), 2.18 (2H, t, J = 6.7 Hz), 2.12-1.98 (3H, m), 1.94-1.82 (1H,m), 1.76-1.41 (6H, m). 542 −78.5 (c = 0.27, MeOH) 99.42% ee 68

(CD₃OD) δ: 7.77-7.68 (2H, m), 7.52 (1H, d, J = 8.6 Hz), 7.29-7.15 (5H,m), 7.11 (1H, dd, J = 7.4, 1.6 Hz), 6.98 (1H, d, J = 8.2 Hz), 6.87 (1H,ddd, J = 8.2, 7.3, 0.9 Hz), 4.94 (1H, d, J = 11.4 Hz), 4.90 (1H, d, J =11.4 Hz), 4.51 (1H, t, J = 7.9 Hz), 3.04-2.65 (10H, m), 2.21 (2H, t, J =6.7 Hz), 2.13- 1.80 (2H, m), 1.79-1.41 (5H, m), 1.24 (6H, d, J = 7.0Hz). 544 +81.6 (c = 0.21, MeOH) 97.64% ee 69

(CD₃OD) δ: 7.76-7.64 (2H, m), 7.52 (1H, d, J = 8.6 Hz) , 7.29-7.14 (5H,m), 7.10 (1H, dd, J = 7.4, 1.6 Hz), 6.97 (1H, d, J = 8.2 Hz), 6.86 (1H,ddd, J = 8.2, 7.3, 0.9 Hz), 4.94 (1H, d, J = 11.4 Hz), 4.89 (1H, d, J =11.4 Hz), 4.44 (1H, t, J = 7.9 Hz), 3.03-2.63 (10H, m), 2.20 (2H, t, J =6.7 Hz), 2.11- 1.79 (2H, m), 1.77-1.42 (5H, m), 1.24 (6H, d, J = 7.0Hz). 544 −92.9 (c = 0.20, MeOH) 99.99% ee

In the following test Examples, the compound of the invention was testedregarding the sGC activating function.

Test Example 1 Maximum Effect of sGC Activating Function

For the assay, Chinese hamster ovary cells (CHO-K1 cells) in which humansGC α subunit and β subunit and mouse cyclic nucleotide gated channel(CNGA2) are stably expressed were used.

CHO-K1 cells in which human sGC and mouse CNGA2 are stably expressedwere cultured at 37° C. in F-12 medium containing 10% (v/v) fetal bovineserum (FBS), penicillin (100 U/mL), streptomycin (100 μg/mL), G418 (250μg/mL), and zeocin (250 μg/mL). The cells were suspended in the culturemedium and seeded onto a 96-well plate, and then cultured at 37° C. for24 hours. After washing with assay buffer 1 (140 mmol/L sodium chloride,5 mmol/L potassium chloride, 0.5 mmol/L magnesium chloride, 0.01 mmol/Lcalcium chloride, 10 mmol/L glucose, 0.4 mmol/L magnesium sulfate, 10mmol/L 4-(2-hydroxyethyl)piperazin-1-ylethane sulfonic acid, and 125μmol/L sulfinpyrazone, pH 7.4), an indicator solution in which FURA2-AMas a fluorescent Ca²⁺ indicator is dissolved at concentration of 5μmol/L in assay buffer 1 was added followed by culture for 60 minutes at37° C. The indicator solution was removed. After washing with assaybuffer 1, the test compound solution was added and incubated for 10minutes at room temperature. The plate was placed in a fluorometer (FlexStation II, Molecular Devices, LLC), and then the intracellular calciumconcentration was measured as fluorescence intensity ratio which isobtained from each excitation wavelength (excitation wavelength of 340nm and 380 nm and detection wavelength of 510 nm).

The test compound solution was prepared by dissolving each of the testcompounds in DMSO to a concentration of 10 mmol/L, and then adding theassay buffer 2 (140 mmol/L sodium chloride, 5 mmol/L potassium chloride,0.5 mmol/L magnesium chloride, 1 mmol/L calcium chloride, 10 mmol/Lglucose, 0.4 mmol/L magnesium sulfate, 10 mmol/L4-(2-hydroxyethyl)piperazin-1-ylethane sulfonic acid, 125 μmol/Lsulfinpyrazone, 100 μmol/L isobutylmethylxanthine, 10 μmol/L1H-[1,2,4]-oxadiazole[4,3-a]quinoxalin-1-one (hereinbelow, ODQ), pH 7.4)for dilution to have test concentration of 10 μmol/L. For the evaluationof a case in which ODQ is not contained, the same evaluation wasperformed except that ODQ is excluded from assay buffer 2. As a controlsolution, a DMSO solution was used instead of the test compoundsolution.

The activity of the test compound corresponds to the increase ratio (%)of the sGC activity at the time of adding the test compound solutionwith respect to the sGC activity at the time of adding the controlsolution, and it was calculated by dividing the fluorescence intensityratio at the time of adding the test compound by the fluorescenceintensity ratio of the control solution and subtracting the sGC activity(100%) at the time of adding the control solution.

The assay results are shown in Table 38 and Table 39.

TABLE 38 Emax (%) ODQ− ODQ+ Test compound (Heme- (Heme- (Example No.)dependent) independent) 1 85.6 103.3 2 97.5 109.0 3 101.6 111.0 4 113.8108.8 5 84.5 86.9 6 126.3 99.9 7 110.1 107.6 8 129.6 101.5 13 64.2 87.214 99.1 101.4 15 101.1 99.9

TABLE 39 16 116.2 97.5 17 114.6 91.8 19 88.7 88.0 22 107.6 100.2 23125.5 104.5 24 134.8 114.2 26 119.4 86.9 27 113.0 96.6 29 140.9 133.0 41109.1 140.3 42 86.7 122.5 43 90.3 107.4 45 95.3 121.3 46 81.3 122.7Cinaciguat 53.0 86.0

In this assay, intracellular cGMP concentration increases as sGC isactivated, and according to opening of CNGA2 following the increase ofcGMP, intracellular Ca²⁺ concentration increases. Thus, SGC activationcan be measured by following the change in intracellular Ca²⁺concentration. Since ODQ is an oxidizing agent which is specific to aheme-binding iron atom and the heme iron atom is oxidized in thepresence of ODQ, heme-dependent sGC activation does not occur. Thus, inthe absence of ODQ, the maximum sGC activating function including theheme-dependent activation can be evaluated while the heme-independentsGC activating function can be evaluated in the presence of ODQ.Meanwhile, both in the presence or absence of ODQ, sGC activity has aconstant value after exhibiting the maximum value at concentration of 10μmol/L or higher for any test compound, including Cinaciguat as aComparative Example, and therefore the activity value at 10 μmol/L wasused as the maximum effect of sGC activity of each test compound (Emax).

As shown in Table 38 and Table 39, all compounds of the presentinvention significantly increased the sGC activity in the presence ofODQ, clearly indicating that they are a heme-independent direct sGCactivating agent. Further, compared to Cinaciguat, the compounds of thepresent invention exhibited higher Emax in any case of having or nothaving ODQ, clearly indicating that it has more excellent sGC activatingfunction than Cinaciguat.

Test Example 2 Heme-Independent Property of sGC Activating Function

For the representative compounds, activity was measured in the samemanner as Test Example 1 at each test concentration of 0.0001, 0.001,0.003, 0.01, 0.03, 0.1, 1, and 10 μmol/L.

The degree of heme-independent property of each test compound withregard to sGC activating function was obtained by dividing, for EC₅₀measured from the concentration-activation curve which has beenestablished from the above, EC₅₀ in the absence of ODQ by EC₅₀ in thepresence of ODQ. Specifically, the smaller the EC₅₀ ratio is, the lessthe change in sGC activating function is, the change in the functionbeing caused by the presence or absence of ODQ, and thus it is found tobe more heme-independent.

EC₅₀ value was obtained by measuring the activity of each compound to betested at concentrations of 0.0001, 0.001, 0.003, 0.01, 0.03, 0.1, 1,and 10 μmol/L and performing the calculation using four-parameterlogistics model using Assay Explorer (Accelrys).

The test results are shown in Table 40.

TABLE 40 Test compound EC₅₀ Ratio (Example No.) (ODQ−/ODQ+) 1 2.86 22.67 3 2.54 4 2.85 6 0.87 7 2.34 8 1.80 14  1.73 15  1.40 23  1.15 27 1.84 29  1.71 Cinaciguat 3.08

As shown in Table 40, it was found that all of the compounds of thepresent invention have lower EC₅₀ ratio than Cinaciguat and are moreheme-independent compared to Cinaciguat.

Test Example 3 Evaluation of Blood Vessel Relaxing Function

The representative compounds of the present invention were evaluated byblood vessel relaxing function according to the following Test Example.In the assay, bleeding from the upper part of a heart of a rat (male,SD) was performed under anesthesia with pentobarbital (30 mg/kg) andthen abdominal aorta was extracted. The connecting tissue adhered aroundblood vessel was removed from the abdominal aorta in an ice-cooledKrebs-Henseleit solution (KH solution) (118 mmol/L sodium chloride, 4.7mmol/L potassium chloride, 1.2 mmol/L magnesium sulfate, 1.2 mmol/Lpotassium dihydrogen phosphate, 25 mmol/L sodium hydrogen carbonate, 2.5mmol/L calcium chloride, and 10 mmol/L glucose, pH 7.4). After that, aring specimen with length of 2 mm was prepared and fixed in 5 mL organbath filled with a KH solution. The KH solution was kept at 37° C. andaerated with a mixture gas of 95% O₂ and 5% CO₂. The specimen wasstabilized for 1 hour with static tension of 1 g. The KH solution wasexchanged twice during that time. The tension on the specimen wasrecorded on a multi-channel recorder via pickup and amplifier. After thestabilization of the specimen, contraction was caused by using 1 μmol/Lphenylephrine (Phe), and cumulative administration of each compound(0.001, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 1000, 10000 nmol/L) wasperformed. For the evaluation of a case in which1H-1,2,4-oxadiazole-(4,3a)-quinoxalin-1-one (ODQ) is contained, 10μmol/L ODQ was added 10 minutes before the Phe addition, and the sameevaluation as above was performed.

EC₅₀ value was calculated using four-parameter logistics model usingAssay Explorer (Accelrys). The test compound solution was dissolved inDMSO such that the concentration of each test compound is 1000 times thefinal concentration.

The test results are shown in Table 41.

TABLE 41 Test compound EC₅₀ Ratio (Example No.) (ODQ−/ODQ+) 15 9.0 295.0 42 4.3 43 5.5 45 3.5 46 5.2 Cinaciguat 12.4

As shown in Table 41, it was found that all of the compounds of thepresent invention have lower EC₅₀ ratio than Cinaciguat and are moreheme-independent than Cinaciguat.

INDUSTRIAL APPLICABILITY

The bicyclic compound of the present invention, a pharmaceuticallyacceptable salt thereof, or a solvate thereof has sGC activatingfunction with excellent heme-independent property, and therefore it isuseful as a pharmaceutical agent for prevention and treatment of variousdisorders that are related with soluble guanylate cyclase, for example,heart failure, hypertension, pulmonary hypertension, and ischemic heartdisease.

The invention claimed is:
 1. A compound of Formula (1):

wherein A represents a C₁-C₃ linear alkylene group, in which onemethylene group is optionally substituted with O or S; n represents aninteger of from 3 to 5; X¹ and X² each independently represent CH or N;W¹ and W² each independently represent a carboxyl group or a tetrazolylgroup; V represents a C₁-C₈ linear or branched alkylene group, in whichone methylene group is optionally substituted with O or S; R representsa group selected from the group consisting of:

in which R¹, R², R³, R⁴ and R⁵ represent a hydrogen atom, a halogenatom, a C₁-C₆ alkyl group which optionally comprises a substituentgroup, a C₁-C₆ alkoxy group, a C₃-C₆ cycloalkyl group, a C₃-C₆cycloalkoxy group, a halo C₁-C₄ alkyl group, a halo C₁-C₄ alkoxy group,a vinyl group which optionally comprises a substituent group, an ethynylgroup which optionally comprises a substituent group, an aryl groupwhich optionally comprises a substituent group on an aromatic ring, anaryloxy group which optionally comprises a substituent group on anaromatic ring, a benzyl group which optionally comprises a substituentgroup on a benzene ring, a phenethyl group which optionally comprises asubstituent group on a benzene ring, a benzyloxy group which optionallycomprises a substituent group on a benzene ring, a benzylsulfanyl groupwhich optionally comprises a substituent group on a benzene ring, abenzylamino group which optionally comprises a substituent group on abenzene ring, a phenyloxymethyl group which optionally comprises asubstituent group on a benzene ring, a phenylsulfanylmethyl group whichoptionally comprises a substituent group on a benzene ring, or aphenylaminomethyl group which optionally comprises a substituent groupon a benzene ring; m represents an integer of 1 or 2; and Y¹ and Y² eachindependently represent methylene, O or S, with the proviso that Y¹ andY² do not simultaneously represent S, a pharmaceutically acceptable saltthereof, or a solvate thereof.
 2. The compound of claim 1, wherein, withregard to R¹, R², R³, R⁴ and R⁵, a substituent group on the C₁-C₆ alkylgroup is a C₁-C₆ alkoxy group, a C₃-C₆ cycloalkyl group, or a C₃-C₆cycloalkoxy group, a substituent group on the vinyl group or ethynylgroup is a C₁-C₆ alkyl group, a C₃-C₆ cycloalkyl group, a phenyl group,a halogenophenyl group, a C₁-C₆ alkylphenyl group, or a halo C₁-C₄alkylphenyl group, a substituent group on the aryl or aryloxy group is ahalogen atom, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a halo C₁-C₄alkyl group, and a substituent group on the benzene ring is a halogenatom, a C₁-C₆ alkyl group, or a halo C₁-C₄ alkyl group, apharmaceutically acceptable salt thereof, or a solvate thereof.
 3. Thecompound of claim 1, wherein, in Formula (1), A is a methylene group,—O—, —CH₂CH₂—, —CH₂O—, —OCH₂—, —CH₂CH₂CH₂—, —CH₂OCH₂—, —CH₂SCH₂—, or—CH₂CH₂O—; n is an integer of from 3 to 5; W¹ and W² are a carboxylgroup; V is —CH₂CH₂—, —CH(CH₃)O— or —CH₂O—; and R is a group selectedfrom the group consisting of:

where R¹ and R² represent a hydrogen atom, a halogen atom, a C₁-C₆ alkylgroup which optionally comprises a substituent group, a C₁-C₆ alkoxygroup, a C₃-C₆ cycloalkyl group, a C₃-C₆ cycloalkoxy group, a halo C₁-C₄alkyl group, a halo C₁-C₄ alkoxy group, a vinyl group which optionallycomprises a substituent group, an ethynyl group which optionallycomprises a substituent group, an aryl group which optionally comprisesa substituent group on an aromatic ring, an aryloxy group whichoptionally comprises a substituent group on an aromatic ring, a benzylgroup which optionally comprises a substituent group on a benzene ring,a phenethyl group which optionally comprises a substituent group on abenzene ring, a benzyloxy group which optionally comprises a substituentgroup on a benzene ring, a benzylsulfanyl group which optionallycomprises a substituent group on a benzene ring, a benzylamino groupwhich optionally comprises a substituent group on a benzene ring, aphenyloxymethyl group which optionally comprises a substituent group ona benzene ring, a phenylsulfanylmethyl group which optionally comprisesa substituent group on a benzene ring, or a phenylaminomethyl groupwhich optionally comprises a substituent group on a benzene ring; mrepresents an integer of 1 or 2; and Y¹ and Y² each independentlyrepresent methylene, O or S, with the proviso that Y¹ and Y² do notsimultaneously represent S, a pharmaceutically acceptable salt thereof,or a solvate thereof.
 4. The compound of claim 1, wherein, in Formula(1), A is a methylene group, —O—, —CH₂CH₂—, —CH₂O—, —OCH₂—, —CH₂CH₂CH₂—,—CH₂OCH₂—, —CH₂SCH₂—, or —CH₂CH₂O—; n is an integer of 4; W¹ and W² area carboxyl group; V is —CH₂CH₂—, —CH(CH₃)O— or —CH₂O—; and R is a groupselected from the group consisting of:

where R¹ and R² represent a hydrogen atom, a halogen atom, a C₁-C₆ alkylgroup which optionally comprises a substituent group, a C₁-C₆ alkoxygroup, a C₃-C₆ cycloalkyl group, a C₃-C₆ cycloalkoxy group, a halo C₁-C₄alkyl group, a halo C₁-C₄ alkoxy group, a vinyl group which optionallycomprises a substituent group, an ethynyl group which optionallycomprises a substituent group, an aryl group which optionally comprisesa substituent group on an aromatic ring, an aryloxy group whichoptionally comprises a substituent group on an aromatic ring, a benzylgroup which optionally comprises a substituent group on a benzene ring,a phenethyl group which optionally comprises a substituent group on abenzene ring, a benzyloxy group which optionally comprises a substituentgroup on a benzene ring, a benzylsulfanyl group which optionallycomprises a substituent group on a benzene ring, a benzylamino groupwhich optionally comprises a substituent group on a benzene ring, aphenyloxymethyl group which optionally comprises a substituent group ona benzene ring, a phenylsulfanylmethyl group which optionally comprisesa substituent group on a benzene ring, or a phenylaminomethyl groupwhich optionally comprises a substituent group on a benzene ring; mrepresents an integer of 1 or 2; and Y¹ and Y² each independentlyrepresent methylene, O or S, with the proviso that Y¹ and Y² do notsimultaneously represent S, a pharmaceutically acceptable salt thereof,or a solvate thereof.
 5. The compound of claim 1, wherein the compoundis selected from the group consisting of:1-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}indane-5-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylicacid,4-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}chromane-7-carboxylicacid,4-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}thiochromane-7-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylicacid,3-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-2,3-dihydrobenzofuran-6-carboxylicacid,4-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-phenylethyl)benzyloxy]phenyl]ethyl]amino}-isochromane-7-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-(2-chlorobenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-[2-[2-(4-Benzyloxybenzyloxy)phenyl]ethyl]-N-(4-carboxybutyl)amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-[2-[2-(4-Benzylsulfanylbenzyloxy)phenyl]ethyl]-N-(4-carboxybutyl)amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-(4-phenoxymethylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-(4-phenylsulfanylmethylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-(4-ethynylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-(4-cyclohexylethynylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-[4-((E)-2-cyclohexylethenyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-[4-(2-cyclohexylethyl)benzyloxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-[trans-4-(2-phenylethyl)cyclohexylmethoxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-[cis-4-(2-phenylethyl)cyclohexylmethoxy]phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-(5,6,7,8-tetrahydronaphthalene-1-ylmethoxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-[2-[2-(3-tert-Butylbenzyloxy)phenyl]ethyl]-N-(4-carboxybutyl)amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-(4-cyclopropylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-(4-Carboxybutyl)-N-[2-[2-(4-isopropylbenzyloxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid,5-{N-[2-[2-[(1R)-1-(4-tert-Butylphenyl)ethoxy]phenyl]ethyl]-N-(4-carboxybutyl)amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid, and5-{N-(4-Carboxybutyl)-N-[2-[2-(indane-5-ylmethoxy)phenyl]ethyl]amino}-5,6,7,8-tetrahydronaphthalene-2-carboxylicacid, a pharmaceutically acceptable salt thereof, or a solvate thereof.6. A pharmaceutical composition, comprising: the compound of claim 1, apharmaceutically acceptable salt thereof, or a solvate thereof; and apharmaceutically acceptable carrier.
 7. A pharmaceutical composition,comprising: the compound of claim 3, a pharmaceutically acceptable saltthereof, or a solvate thereof; and a pharmaceutically acceptablecarrier.
 8. A pharmaceutical composition, comprising: the compound ofclaim 4, a pharmaceutically acceptable salt thereof, or a solvatethereof; and a pharmaceutically acceptable carrier.
 9. A pharmaceuticalcomposition, comprising: the compound of claim 5, a pharmaceuticallyacceptable salt thereof, or a solvate thereof; and a pharmaceuticallyacceptable carrier.
 10. A pharmaceutical composition, comprising: thecompound of claim 2, a pharmaceutically acceptable salt thereof, or asolvate thereof; and a pharmaceutically acceptable carrier.